Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.

Impact of Targeted Systemic Therapy and Radiotherapy on Patients Undergoing Spine Surgery for Metastatic Renal Cell Carcinoma.

BACKGROUND: In patients undergoing spine surgery for renal cell carcinoma (RCC), we sought to: (1) describe patterns of postoperative targeted systemic therapy and radiotherapy (RT), (2) compare perioperative outcomes among those treated with targeted systemic therapy to those without, and (3) evaluate the impact of targeted systemic therapy and/or RT on overall survival (OS) and local recurrence (LR). METHODS: A single-institution, retrospective cohort study of patients undergoing spine surgery for metastatic RCC from 2010 to 2021 was undertaken. Treatment groups were RT alone, targeted systemic therapy alone, dual therapy consisting of RT and targeted systemic therapy, and neither therapy. Multivariable Cox regression controlled for age, race, sex, insurance, and preoperative targeted systemic therapy. RESULTS: Forty-nine patients underwent spine surgery for RCC. Postoperatively, 4 patients (8%) received RT alone, 19 (38.8%) targeted systemic therapy alone, 12 (24.5%) dual therapy, and 13 (28.6%) neither. All groups were similar in demographics, preoperative Karnofsky Performance Score (P = 0.372), tumor size (P = 0.413), readmissions (P = 0.884), complications (P = 0.272), Karnofsky Performance Score (P = 0.466), and Modified McCormick Scale (P = 0.980) at last follow-up. Higher 1-year survival was found in dual therapy (83.3%) compared with other therapies. OS was significantly longer in patients with dual therapy compared with other therapies (log-rank; P = 0.010). Multivariate Cox regression (HR = 0.08, 95% CI = 0.02-0.31, P < 0.001) showed longer OS in dual therapy compared with other therapies. Seven patients (14.3%) experienced LR, and a similar time to LR was found between groups (log-rank; P = 0.190). CONCLUSION: In patients undergoing metastatic spine surgery for RCC, postoperative dual therapy demonstrated significantly higher 1-year survival and OS compared with other therapies. CLINICAL RELEVANCE: Multidisciplinary management of metastatic RCC is necessary to ensure timely implementation of targeted systemic therapy and RT to improve outcomes.

Frequency of Comfort Care and Palliative Care Consultation after ST-elevation Myocardial Infarction.

INTRODUCTION: ST-elevation myocardial infarction (STEMI) remains a leading cause of death despite advances in revascularization and post-STEMI care. Especially for patients with a poor prognosis, there is increasing emphasis on comfort-focused care. METHODS: We conducted a single-center retrospective cohort study of patients with STEMI at a large tertiary care academic medical center, abstracting patient-level data, causes of death, and use of palliative care consultation from the medical records. We sought to investigate the frequency of comfort-focused approaches and palliative care consultation after STEMI. RESULTS: A total of 536 patients presented with or were transferred with STEMI from January 2010 to July 2018, of whom 61/536 (11.4%) died during index hospitalization. Among those who underwent percutaneous intervention (PCI), the in-hospital mortality rate was 6.8%. Median (IQR) and time to death was 2 (0-6) days. Among those who died, 25/61 (41%) were treated with mechanical circulatory support (MCS). A total of 25/61 (41%) patients died following transition to a comfort-focused approach. Rate of MCS utilization during hospitalization was higher in the group that was ultimately transitioned to comfort-focused measures than the group who received full treatment measures. Palliative care was consulted in the case of 6/61 (9.8%) patients. Median time to consultation was 5 (1-7) days and time to death was 6.5 (2-28) days. DISCUSSION: Transition to comfort-focused care before death after STEMI is common, particularly in those with cardiogenic shock and/or treated with MCS, highlighting the critical status of such patients. Although increasingly employed in recent years, palliative care consults remain rare and are often employed late in the hospitalization.

Molecular detection of Coxiella burnetii in ticks collected from animals and the environment in Uganda.

AIMS: Coxiella burnetii is a highly infectious organism that is easily spread through aerosols causing Q fever in humans. Ticks can harbour and transmit C. burnetii to animals, contributing to disease maintenance. Our aim was to examine the presence of C. burnetii in ticks in Uganda. METHODS AND RESULTS: In this study, ticks were collected from five Ugandan districts and tested by real-time PCR for C. burnetii (Coxiella outer membrane protein 1 gene). A total of 859 tick pools (9602 individual ticks) were tested, and pool positivity for C. burnetii was 5.5% (n = 47). Pooled prevalence differed by district; the highest was Luwero (7.3%), then Gulu (6.6%), and Kasese had the lowest (1.3%). However, district variation was not statistically significant (Fisher's exact = 0.07). Ticks collected from dogs and cats had the highest positivity rates [23/47, (48.9%)] followed by livestock (cattle, goats, sheep, and pigs) [18/47, (38.3%)] and vegetation [6/47, (12.8%)]. Haemaphysalis elliptica had the highest infection rates, followed by Rhipicephalus appendiculatus, Amblyomma variegatum and Rhipicephalus decoloratus had similar prevalence. CONCLUSIONS: Although ticks are not the primary transmitters of C. burnetii to humans, pathogen detection in ticks can be an indirect indicator of risk among animal hosts. Vulnerable populations, including occupations with close animal contact such as farming, butchery, and veterinary practice, have an increased risk of C. burnetii exposure. Veterinarians and clinicians should be aware that C. burnetii may cause human and animal illness in these regions.

Addressing Burn Hypertrophic Scar Symptoms Earlier: Laser Scar Revision May Begin as Early as 3-6 Months After Injury.

OBJECTIVES: Fractional ablative CO2 laser (FLSR) is used to treat hypertrophic scars (HTSs) resulting from burn injuries, which are characterized by factors, such as erythema, contracture, thickness, and symptoms of pain and itch. Traditionally, waiting a year after injury for scar maturation before starting laser treatment has been recommended; however, the potential benefits of earlier intervention have gained popularity. Still, the optimal timing for beginning laser intervention in patients with HTSs remains uncertain. This study aims to evaluate the ideal timing for the initiation of FLSR for HTSs using several qualitative and quantitative assessment measures. It was hypothesized that early intervention would lead to similar improvement trends as later intervention, however, would be more ideal due to the shortened time without symptom relief for patients. METHODS: Patients who received three or more laser treatment sessions and completed both pre- and posttreatment evaluations were included in this analysis (n = 69). FLSR treatment was administered at 4-8-week intervals. Patients starting treatment before 6 months after injury were classified as the early-stage intervention group and those beginning treatment at 6-12 months after injury were classified as the late-stage intervention group. Demographic data, including the age of patients at the time of first treatment, age of scars at the time of first treatment, biological sex, ethnicity, Fitzpatrick skin type, and use of laser-assisted drug delivery, were collected by retrospective chart review. Patients were evaluated on six subjective scales and objectively for scar stiffness with durometry. For all scales, higher scores indicate worse scars. A two-way ANOVA, Student's t-test, and Mann-Whitney U-test were used to compare scores from the pre- to posttreatment evaluations. RESULTS: There were no significant differences between the groups for any of the demographic or scar-specific variables; thus, differences in outcome can be attributed to the timing of intervention. Both groups demonstrated an improvement in scars with treatment over time (p < 0.05). Both early- and middle-stage initiation showed scar symptom improvement in five out of six scales. In the late-stage intervention, the Patient and Observer Scar Assessment Scale-Patient average score did not show improvement. In the early-stage intervention, the Vancouver Scar Scale total did not show improvement. Quantitative evaluation of scar stiffness by durometry did not show symptom improvement in either group. The Scar Comparison Scale demonstrated the greatest improvement across groups. CONCLUSION: Laser treatment led to scar improvement in at least one scale at each stage of initiation. Both intervention timelines resulted in equivalent outcomes, and early intervention should be considered when initiating FLSR treatment in burn scars to alleviate symptoms earlier.

Neonatal Diazepam Exposure Decreases Dendritic Arborization and Spine Density of Cortical Pyramidal Neurons in Rats.

OBJECTIVE: Benzodiazepines are extensively utilized in pediatric anesthesia and critical care for their anxiolytic and sedative properties. However, preclinical studies indicate that neonatal exposure to GABAergic drugs, including benzodiazepines, leads to long-term cognitive deficits, potentially mediated by altered GABAergic signaling during brain development. This preclinical study investigated the impact of early-life diazepam exposure on cortical neuronal morphology, specifically exploring dendritic arborization and spine density, crucial factors in synaptogenesis. METHODS: Male and female Sprague Dawley rat pups were exposed to a single neonatal dose of diazepam (30 mg/kg) or vehicle on postnatal day (PND) 7. Golgi-Cox staining was used to assess cortical pyramidal neuron development at 4 developmental stages: neonatal (PND8), infantile (PND15), juvenile (PND30), and adolescence (PND42). Animals were randomized equally to 4 groups: male-vehicle, male-diazepam, female-vehicle, and female-diazepam. Neuronal morphology was evaluated after reconstruction in neurolucida, and dendritic spine density was analyzed through high-power photomicrographs using ImageJ. RESULTS: Diazepam exposure resulted in decreased dendritic complexity in both sexes, with reduced arborization and spine density observed in cortical pyramidal neurons. Significant differences were found at each developmental stage, indicating a persistent impact. Dendritic length increased with age but was attenuated by diazepam exposure. Branching length analysis revealed decreased complexity after diazepam treatment. Spine density at PND42 was significantly reduced in both apical and basal dendrites after diazepam exposure. CONCLUSIONS: Neonatal diazepam exposure adversely affected cortical pyramidal neuron development, leading to persistent alterations in dendritic arborization and spine density. These structural changes suggest potential risks associated with early-life diazepam exposure. Further research is needed to unravel the functional consequences of these anatomic alterations.

The clinical impact of estimating low-density lipoprotein cholesterol (LDL-C) using different equations in the general population.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD). Friedewald, Sampson, and Martin-Hopkins equations are used to calculate LDL-C. This study compares the impact of switching between these equations in a large geographically defined population. MATERIALS AND METHODS: Data for individuals who had a lipid panel ordered clinically between 2010 and 2019 were included. Comparisons were made across groups using the two-sample t-test or chi-square test as appropriate. Discordances between LDL measures based on clinically actionable thresholds were summarized using contingency tables. RESULTS: The cohort included 198,166 patients (mean age 54 years, 54% female). The equations perform similarly at the lower range of triglycerides but began to diverge at a triglyceride level of 125 mg/dL. However, at triglycerides of 175 mg/dL and higher, the Martin-Hopkins equation estimated higher LDL-C values than the Samson equation. This discordance was further exasperated at triglyceride values of 400 to 800 mg/dL. When comparing the Sampson and Friedewald equations, at triglycerides are below 175 mg/dL, 9% of patients were discordant at the 70 mg/dL cutpoint, whereas 42.4% were discordant when triglycerides are between 175 and 400 mg/dL. Discordance was observed at the clinically actionable LDL-C cutpoint of 190 mg/dL with the Friedewald equation estimating lower LDL-C than the other equations. In a high-risk subgroup (ASCVD risk score > 20%), 16.3% of patients were discordant at the clinical cutpoint of LDL-C < 70 mg/dL between the Sampson and Friedewald equations. CONCLUSIONS: Discordance at clinically significant LDL-C cutpoints in both the general population and high-risk subgroups were observed across the three equations. These results show that using different methods of LDL-C calculation or switching between different methods could have clinical implications for many patients.

Engineering programmable material-to-cell pathways via synthetic notch receptors to spatially control differentiation in multicellular constructs.

Synthetic Notch (synNotch) receptors are genetically encoded, modular synthetic receptors that enable mammalian cells to detect environmental signals and respond by activating user-prescribed transcriptional programs. Although some materials have been modified to present synNotch ligands with coarse spatial control, applications in tissue engineering generally require extracellular matrix (ECM)-derived scaffolds and/or finer spatial positioning of multiple ligands. Thus, we develop here a suite of materials that activate synNotch receptors for generalizable engineering of material-to-cell signaling. We genetically and chemically fuse functional synNotch ligands to ECM proteins and ECM-derived materials. We also generate tissues with microscale precision over four distinct reporter phenotypes by culturing cells with two orthogonal synNotch programs on surfaces microcontact-printed with two synNotch ligands. Finally, we showcase applications in tissue engineering by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined micropatterns. These technologies provide avenues for spatially controlling cellular phenotypes in mammalian tissues.

National Beef Quality Audit-2022: in-plant assessments of quality and yield determining carcass characteristics of fed steers and heifers.

The National Beef Quality Audit - 2022 serves as a benchmark of the current fed steer and heifer population of the U.S. beef industry and allows comparison to previous audits as a method of monitoring industry progress. In-plant cooler assessments and collections of beef carcass data took place from July 2021 to November 2022. During in-plant evaluations, 10% of 1-d production was surveyed for quality and yield indicating characteristics of fed beef carcasses (n = 9,746 beef carcasses). Distributions of sex classes among sampled carcasses were steer (65.0%) and heifer (35.0%), whereas distributions of breed type were native (87.7%), dairy (11.3%), and Bos indicus (0.9%). Mean values were observed for USDA Yield Grades (YG; 3.3), USDA Quality Grade (QG; Choice16), marbling score (Small98), ribeye area (91.0 cm2), adjusted fat thickness (1.49 cm), hot carcass weight (401.9 kg), and KPH (2.5%). Mean overall maturity was A66, with a mean lean maturity of A56 and mean skeletal maturity of A72. There were 28.1% of carcasses identified for use in a USDA-certified beef G-Schedule Program. Defects, such as dark cutting and blood splash, were observed at 1.8% and 0.5%, respectively. Distributions of USDA YG were YG 1 (8.2%), YG 2 (30.7%), YG 3 (40.2%), YG 4 (16.6%), and YG 5 (4.3%). USDA QGs were observed at 7.5% Prime, 69.2% Choice, 16.4% Select, and 6.8% other. The results of this study provide an updated look at the current grading trends of beef carcasses in the United States to drive progress in the fed beef industry.

Small molecule substrates for the rapid quantification of acyl transfer activity of nylon hydrolase NylCA.

The widespread use of polyamides such as nylons has led to the accumulation of nylon waste, which is particularly resistant to decomposition due to the intrinsic stability of the amide bond. New methods are required for the true recycling of these waste materials by depolymerization. Enzymes that are capable of hydrolyzing polyamides have been proposed as biocatalysts that may be suitable for this application. NylC is an enzyme that can mediate the hydrolysis of aminohexanoic acid oligomers, and to some extent, bulk polymers. However, current assays to characterize the activity of this enzyme require long reaction times and/or rely on secondary reactions to quantify hydrolysis. Herein, we have designed structurally-optimized small molecule chromogenic esters that serve as substrate analogues for monitoring NylC acyltransferase activity in a continuous manner. This assay can be performed in minutes at room temperature, and the substrate N-acetyl-GABA-pNP ester (kcat = 0.37 s-1, KM = 256 µM) shows selectivity for NylC in complex biological media. We also demonstrate that activity towards this substrate analogue correlates with amide hydrolysis, which is the primary activity of this enzyme. Furthermore, our screening of substrate analogues provides insight into the substrate specificity of NylC, which is relevant to biocatalytic applications.

Copper deficiency myelopathy mimicking cervical spondylitic myelopathy: a systematic review of the literature with case report.

BACKGROUND AND CONTEXT: Copper deficiency myelopathy (CDM) is a rare disease that can present with spastic quadriparesis and sensory ataxia. As a result, it can precisely mimic cervical spondylitic myelopathy (CSM). Copper deficiency may be seen following gastric bypass surgery, malabsorption syndromes such as celiac disease, and with excessive exogenous zinc intake. We present a systematic review of the literature for CDM and an illustrative case. PURPOSE: Provide a systematic review of CDM to highlight the importance of recognizing the consideration of CDM in patients presenting to a spine surgeon with myelopathy that progress despite adequate surgical decompression, or myelopathy concomitant with cytopenia, thus requiring further workup. STUDY DESIGN/SETTING: Retrospective medical record review and systematic review of the literature PATIENT SAMPLE: PubMed and Ovid-Embase database search was conducted in July 2022 OUTCOME MEASURES: Self-reported measures include PRISMA flow diagram for retrospective review; Physiological measures include retrospective review of MRI imaging of cervical spine; alternate demographic and laboratory value data extracted via literature review METHODS: A PubMed and Ovid-Embase database search was conducted in July 2022 searching for "copper deficiency myelopathy (MeSH)" from 2000 to 2022 via PRISMA guidelines. Following title and abstract review, the following data was extracted from full text: age, sex, etiology, hematological values upon presentation (mean corpuscular volume, white blood count, platelet count, and hemoglobin level), metal serum studies (serum copper, ceruloplasmin, and zinc), 24-hour collection of copper and zinc, and distinct radiographic findings on MRI. RESULTS: A total of 116 studies were included in this review which contained 198 cases of copper deficiency myelopathy. The mean age was 53.57 ± 14.14 years, with the majority being females (63.8%). The most common etiology was prior gastric surgery (n=55, 36.2 %) followed by excessive zinc consumption from the use of zinc denture cream (n=39, 19.9%). The mean serum copper was 15.67 ± 17.84 (normal=80.0-155.0) mcg/dL and mean ceruloplasmin was 6.43 ± 5.25 (normal=16-45) mg/dL. In spite of appropriate treatment with copper supplementation, only 47 cases (24%) reported improvement in neurological status, and only 10 (5.1%) recovered to baseline. A hyperintense T2 signal abnormality resembling an inverted "v" in the dorsal columns was the most common radiographic abnormality. CONCLUSION: Pertinent risk factors for copper deficiency myelopathy include prior upper gastrointestinal surgery, zinc excess, and malabsorption. Characteristic laboratory and imaging findings include cytopenia, low serum copper and ceruloplasmin, and distinct inverted "v" T2 signal hyperintensity in the dorsal columns. The neurologic deterioration with copper deficiency will progress in spite of decompressive surgery, and can be devastating and irreversible even with copper supplementation, reinforcing the importance of early detection. We thus recommend patients with myelopathy presenting with a history of gastric bypass, malabsorption syndromes, excessive zinc exposure, cytopenia, or imaging resembling an inverted "v" shaped hyperintense T2 MRI signal in the dorsal columns, should first undergo blood tests for copper, ceruloplasmin, and B12 levels prior to surgical consideration.

Thiol-Functionalized Adsorbents through Atomic Layer Deposition and Vapor-Phase Silanization for Heavy Metal Ion Removal.

The removal of toxic heavy metal ions from water resources is crucial for environmental protection and public health. In this study, we address this challenge by developing a surface functionalization technique for the selective adsorption of these contaminants. Our approach involves atomic layer deposition (ALD) followed by vapor-phase silanization of porous substrates. We utilized porous silica gel powder (∼100 µm particles, 89 m2/g surface area, ∼30 nm pores) as an initial substrate. This powder was first coated with ∼0.5 nm ALD Al2O3, followed by vapor-phase grafting of a thiol-functional silane. The modified powder, particularly in acidic conditions (pH = 4), showed high selectivity in adsorbing Cd(II), As(V), Pb(II), Hg(II), and Cu(II) heavy metal ions in mixed ion solutions over common benign ions (e.g., Na, K, Ca, and Mg). Langmuir adsorption isotherms and breakthrough adsorption studies were conducted to assess heavy metal binding affinity and revealed the order of Cd(II) < Pb(II) < Cu(II) < As(V) < Hg(II), with a significantly higher affinity for As(V) and Hg(II) ions. Time-dependent uptake studies demonstrated rapid removal of heavy metal ions from aqueous environments, with Hg(II) exhibiting the fastest adsorption kinetics on thiol-modified surfaces. These findings highlight the potential of ALD and vapor-phase silanization to create effective adsorbents for the targeted removal of hazardous contaminants from water.

Shifting institutional culture to develop climate solutions with Open Science.

To address our climate emergency, "we must rapidly, radically reshape society"-Johnson & Wilkinson, All We Can Save. In science, reshaping requires formidable technical (cloud, coding, reproducibility) and cultural shifts (mindsets, hybrid collaboration, inclusion). We are a group of cross-government and academic scientists that are exploring better ways of working and not being too entrenched in our bureaucracies to do better science, support colleagues, and change the culture at our organizations. We share much-needed success stories and action for what we can all do to reshape science as part of the Open Science movement and 2023 Year of Open Science.

Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving.

BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

Hybrid magnon-phonon localization enhances function near ferroic glassy states.

Ferroic materials on the verge of forming ferroic glasses exhibit heightened functionality that is often attributed to competing long- and short-range correlations. However, the physics underlying these enhancements is not well understood. The Ni45Co5Mn36.6In13.4 Heusler alloy is on the edge of forming both spin and strain glasses and exhibits magnetic field-induced shape memory and large magnetocaloric effects, making it a candidate for multicaloric cooling applications. We show using neutron scattering that localized magnon-phonon hybrid modes, which are inherently spread across reciprocal space, act as a bridge between phonons and magnons and result in substantial magnetic field-induced shifts in the phonons, triple the caloric response, and alter phase stability. We attribute these modes to the localization of phonons and magnons by antiphase boundaries coupled to magnetic domains. Because the interplay between short- and long-range correlations is common near ferroic glassy states, our work provides general insights on how glassiness enhances function.

A Nude Mouse Model of Xenografted Hypertrophic Scar Cells to Test Therapeutics in the Skin.

BACKGROUND: Existing animal models for testing therapeutics in the skin are limited. Mouse and rat models lack similarity to human skin in structure and wound healing mechanism. Pigs are regarded as the best model with regards to similarity to human skin; however, these studies are expensive, time-consuming, and only small numbers of biologic replicates can be obtained. In addition, local-regional effects of treating wounds that are closely adjacent to one-another with different treatments make assessment of treatment effectiveness difficult in pig models. Therefore, here, a novel nude mouse model of xenografted porcine hypertrophic scar (HTS) cells was developed. This model system was developed to test if supplying hypo-pigmented cells with exogenous alpha melanocyte stimulating hormone (α-MSH) will reverse pigment loss in vivo. METHODS: Dyschromic HTSs were created in red Duroc pigs. Epidermal scar cells (keratinocytes and melanocytes) were derived from regions of hyper-, hypo-, or normally pigmented scar or skin and were cryopreserved. Dermal fibroblasts (DFs) were isolated separately. Excisional wounds were created on nude mice and a grafting dome was placed. DFs were seeded on day 0 and formed a dermis. On day 3, epidermal cells were seeded onto the dermis. The grafting dome was removed on day 7 and hypo-pigmented xenografts were treated with synthetic α-MSH delivered with microneedling. On day 10, the xenografts were excised and saved. Sections were stained using hematoxylin and eosin hematoxylin and eosin (H&E) to assess xenograft structure. RNA was isolated and quantitative real-time polymerase chain reaction (qRT-PCR) was performed for melanogenesis-related genes TYR, TYRP1, and DCT. RESULTS: The seeding of HTSDFs formed a dermis that is similar in structure and cellularity to HTS dermis from the porcine model. When hyper-, hypo-, and normally-pigmented epidermal cells were seeded, a fully stratified epithelium was formed by day 14. H&E staining and measurement of the epidermis showed the average thickness to be 0.11 ± 0.07 µm vs. 0.06 ± 0.03 µm in normal pig skin. Hypo-pigmented xenografts that were treated with synthetic α-MSH showed increases in pigmentation and had increased gene expression of TYR, TYRP1, and DCT compared to untreated controls (TYR: 2.7 ± 1.1 vs. 0.3 ± 1.1; TYRP1: 2.6 ± 0.6 vs. 0.3 ± 0.7; DCT 0.7 ± 0.9 vs. 0.3 ± 1-fold change from control; n = 3). CONCLUSIONS: The developed nude mouse skin xenograft model can be used to study treatments for the skin. The cells that can be xenografted can be derived from patient samples or from pig samples and form a robust dual-skin layer containing epidermis and dermis that is responsive to treatment. Specifically, we found that hypo-pigmented regions of scar can be stimulated to make melanin by synthetic α-MSH in vivo.

Seizure-Related Falls and Near Falls in LGI1-IgG Autoimmune Encephalitis.

Objectives: To study the frequency, causes, and consequences of seizure-related falls and near falls in LGI1-IgG autoimmune encephalitis. Methods: We retrospectively reviewed 136 patients seen at Mayo Clinic with (1) LGI1-IgG seropositivity, (2) clinical phenotypes compatible with LGI1-IgG autoimmune encephalitis, and (3) falls or near falls related to seizures. The clinical documentation, MRI, and EEG data were collected and reviewed. Results: In this cohort of 136 patients, 27% (n = 36) had falls or near falls related to seizures. The median age was 67 years (range 49-86 years) and 23/36 (64%) were male. Facio-brachio-crural dystonic seizures (21/36, 58%) and drop attacks (9/36, 25%) were the most common causes. Seizure-related falls resulted in injuries in 18/30 (60%), ranging from skin lacerations, joint dislocations, bone fractures to life-threatening intracranial hemorrhage. The injuries occurred most with drop attacks 8/9 (89%). Seizure-related falls or near falls resolved with immunotherapy in 24/32 (75%) whereas the responsiveness to anti-seizure medication alone was poor (4/32, 13%). Discussion: Our study demonstrates that seizure-related falls and near falls are common in LGI1-IgG autoimmune encephalitis. Early diagnosis, prompt immunotherapy initiation, and proper counseling are key to improving functional outcomes and preventing secondary injuries.

Unconventional acoustic wave propagation transitions induced by resonant scatterers in the high-density limit.

Experiments on ultrasound propagation through a gel doped with resonant encapsulated microbubbles provided evidence for a discontinuous transition between wave propagation regimes at a critical excitation frequency. Such behavior is unlike that observed for soft materials doped with non-resonant air or through liquid foams, and disagrees with a simple mixture model for the effective sound speed. Here, we study the discontinuous transition by measuring the transition as a function of encapsulated microbubble volume fraction. The results show the transition always occurs in the strong-scattering limit (l/λ < 1, l and λ are the mean free path and wavelength, respectively), that at the critical frequency the effective phase velocity changes discontinuously to a constant value with increasing microbubble volume fraction, and the measured critical frequency shows a power law dependence on microbubble volume fraction. The results cannot be explained by multiple scattering theory, viscous effects, mode decoupling, or a critical density of states. It is hypothesized the transition depends upon the microbubble on-resonance effective properties, and we discuss the results within the context of percolation theory. The results shed light on the discontinuous transition's physics, and suggest soft materials can be engineered in this manner to achieve a broad range of physical properties with potential application in ultrasonic actuators and switches.

2-Aminopyridines as Potent and Selective Nav1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model.

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Nav1.8 sodium channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.

Surveillance outcomes of respiratory pathogen infections during the 2021-2022 season among U.S. Military Health System beneficiaries, October 3, 2021-October 1, 2022.

The Department of Defense Global Respiratory Pathogen Surveillance Program conducts continuous surveillance for influenza, severe acute respiratory syndrome 2 (SARS-CoV-2), and other respiratory pathogens at 104 sentinel sites across the globe. These sites submitted 65,475 respiratory specimens for clinical diagnostic testing during the 2021-2022 surveillance season. The predominant influenza strain was influenza A(H3N2) (n=777), of which 99.9% of strains were in clade 3C.2a1b.2a2. A total of 21,466 SARSCoV-2-positive specimens were identified, and 12,225 of the associated viruses were successfully sequenced. The Delta variant predominated at the start of the season, until December 2021, when Omicron became dominant. Most circulating SARS-CoV-2 viruses were subsequently held by Omicron sublineages BA.1, BA.2, and BA.5 during the season. Clinical manifestation, obtained through a self-reported questionnaire, found that cough, sinus congestion, and runny nose complaints were the most common symptoms presenting among all pathogens. Sentinel surveillance can provide useful epidemiological data to supplement other disease monitoring activities, and has become increasingly useful with increasing numbers of individuals utilizing COVID-19 rapid self-test kits and reductions in outpatient visits for routine respiratory testing.