Normscan: open-source Python software to create average models from CT scans.

PURPOSE: Age-matched average 3D models facilitate both surgical planning and intraoperative guidance of cranial birth defects such as craniosynostosis. We aimed to develop an algorithm that accepts any number of CT scans as input and generates highly accurate, average models with minimal user input that are ready for 3D printing and clinical use. METHODS: Using a compiled database of 'normal' pediatric computed tomography (CT) scans, we report Normscan, an open-source platform built in Python that allows users to generate normative models of CT scans through user-defined landmarks. We use the basion, nasion, and left and right porions as anatomical landmarks for initial correspondence and then register the models using the iterative closest points algorithm before downstream averaging. RESULTS: Normscan is fast and easy to use via our user interface and also creates highly accurate average models of any number of input models. Additionally, it is highly repeatable, with coefficients of variance for the surface area and volume of the average model being less than 3% across ten independent trials. Average models can then be 3D printed and/or visualized in augmented reality. CONCLUSIONS: Normscan provides an end-to-end pipeline for the creation of average models of skulls. These models can be used for the generation of databases of specific demographic anatomical models as well as for intraoperative guidance and surgical planning. While Normscan was designed for craniosynostosis repair, due to the modular nature of the algorithm, Normscan has many applications in other areas of surgical planning and research.

Design, synthesis, and spectroscopic profiling of novel coumarin dyes: Investigating solvent sensitivity and photophysical properties.

Coumarin dyes are highly versatile and widely employed as fluorescent chemosensors in a variety of fields, including molecular imaging, bioorganic chemistry, analytical chemistry, materials chemistry, biology, and medical science. Thanks to their outstanding photostability and high quantum yield, they represent an ideal choice for developing sensitive and selective sensing platforms. In this study, we successfully designed and synthesized four new dyes based on the coumarin dye molecular skeleton, investigating their solvent sensitivity and spectroscopic properties. Our novel coumarin dyes were synthesized by a straightforward approach, reacting coumarin-3-carboxylic acid succinimidyl ester derivatives with corresponding amines in 1,4-dioxane as a solvent. We carefully monitored the completion of the reactions using thin-layer chromatography (TLC) and characterized these dyes using spectral and elemental analyses. We further investigated the UV, fluorescence, time-correlated single photon counting (TCSPC) technique and time-resolved spectroscopy (TRES) of these dyes in different solvents and on polymer film poly(methyl methacrylate) (PMMA). The quantum yield of the synthesized dyes was determined, with values observed to range between 0.55 and 0.94. Most of the dye-solvent and dye-polymer combinations exhibited single exponential decay, with lifetimes ranging from 2.3 to 3 ns. Minor deviations from single exponential behavior were observed for most of the dyes in toluene, while significant deviations were observed for coumarin dyes with piperazine moiety. We have provided a rationalization of these results in terms of the chemical functionalities of the various dyes. Furthermore, we investigated the effect of interactions between 7-methoxy-2-oxo-N-(2-(piperazin-1-yl)ethyl)-2H-chromene-3-carboxamide and silica nanoparticles (Ludox) on the spectroscopic properties of these dyes, with charge transfer being one possible mechanism contributing to the behavior of the dyes. Additionally, we explored the effect of trifluoroacetic acid (TFA) on the dyes' emission intensity and fluorescence decay. Based on our UV and fluorescence measurements of the dyes in different solvents, we have concluded that these dyes can create excellent donor-acceptor pairs for our upcoming fluorescence resonance energy transfer (FRET) experiments.

Transient plasma membrane disruption induced calcium waves in mouse and human corneal epithelial cells.

The purpose of this study was to examine transient plasma membrane disruptions (TPMDs) and TPMD-induced Ca++ waves (TPMD Ca++ Wvs) in human and mouse corneal epithelium (HCEC and MCEC). A multi-photon microscope was used to create laser-induced TPMDs in single cultured cells and in intact ex vivo and in vivo MCECs and ex vivo human cornea rim HCECs. Eye rubbing-induced TPMDs were studied by gentle rubbing with a cotton tipped applicator over a closed eyelid in ex vivo and in vivo MCECs. Ca++ sources for TPMD-induced Ca++ waves were explored using Ca++ channel inhibitors and Ca++-free media. TPMDs and TPMD Ca++ Wvs were observed in all cornea epithelial models examined, often times showing oscillating Ca++ levels. The sarcoplasmic reticulum Ca++ ATPase inhibitors thapsigargin and CPA reduced TPMD Ca++ Wvs. TRP V1 antagonists reduced TPMD Ca++ Wvs in MCECs but not HCECs. Ca++-free medium, 18α-GA (gap junction inhibitor), apyrase (hydrolyzes ATP), and AMTB (TRPM8 inhibitor) did not affect TPMD Ca++ Wvs. These results provide a direct demonstration of corneal epithelial cell TPMDs and TPMDs in in vivo cells from a live animal. TPMDs were observed following gentle eye rubbing, a routine corneal epithelial cell mechanical stress, indicating TPMDs and TPMD Ca++ Wvs are common features in corneal epithelial cells that likely play a role in corneal homeostasis and possibly pathophysiological conditions. Intracellular Ca++ stores are the primary Ca++ source for corneal epithelial cell TPMD Ca++ Wvs, with TRPV1 Ca++ channels providing Ca++ in MCECs but not HCECs. Corneal epithelial cell TPMD Ca++ Wv propagation is not influenced by gap junctions or ATP.

Bioresorbable, wireless, passive sensors for continuous pH measurements and early detection of gastric leakage.

Continuous monitoring of biomarkers at locations adjacent to targeted internal organs can provide actionable information about postoperative status beyond conventional diagnostic methods. As an example, changes in pH in the intra-abdominal space after gastric surgeries can serve as direct indicators of potentially life-threatening leakage events, in contrast to symptomatic reactions that may delay treatment. Here, we report a bioresorbable, wireless, passive sensor that addresses this clinical need, designed to locally monitor pH for early detection of gastric leakage. A pH-responsive hydrogel serves as a transducer that couples to a mechanically optimized inductor-capacitor circuit for wireless readout. This platform enables real-time monitoring of pH with fast response time (within 1 hour) over a clinically relevant period (up to 7 days) and timely detection of simulated gastric leaks in animal models. These concepts have broad potential applications for temporary sensing of relevant biomarkers during critical risk periods following diverse types of surgeries.

Quantifying Microvascular Structure in Healthy and Infarcted Rat Hearts Using Optical Coherence Tomography Angiography.

Myocardial infarction (MI) is a life-threatening medical emergency resulting in coronary microvascular dysregulation and heart muscle damage. One of the primary characteristics of MI is capillary loss, which plays a significant role in the progression of this cardiovascular condition. In this study, we utilized optical coherence tomography angiography (OCTA) to image coronary microcirculation in fixed rat hearts, aiming to analyze coronary microvascular impairment post-infarction. Various angiographic metrics are presented to quantify vascular features, including the vessel area density, vessel complexity index, vessel tortuosity index, and flow impairment. Pathological differences identified from OCTA analysis are corroborated with histological analysis. The quantitative assessments reveal a significant decrease in microvascular density in the capillary-sized vessels and an enlargement for the arteriole/venule-sized vessels. Further, microvascular tortuosity and complexity exhibit an increase after myocardial infarction. The results underscore the feasibility of using OCTA to offer qualitative microvascular details and quantitative metrics, providing insights into coronary vascular network remodeling during disease progression and response to therapy.

The dimensionality of vaccination intentions: One strain or multiple strains?

OBJECTIVE: People likely have different attitudes toward different vaccines (e.g., they may hold a positive attitude toward the measles, mumps, and rubella-vaccine while simultaneously hold a neutral attitude toward the flu shot). To examine the dimensionality of vaccination intentions, we measured vaccination intentions toward 16 different diseases. We hypothesized that people differentiate between child-directed vaccination intentions and self-directed vaccination intentions. Furthermore, we hypothesized that some commonly studied factors (e.g., trust in authorities and fear of needles) might have different associations with the two subtypes of vaccination intentions. METHOD: We used data from a nationally representative sample of the Netherlands collected in 2021. We used exploratory (N = 865) and confirmatory factor analysis (N = 865) to evaluate the dimensionality hypothesis and used linear hypothesis tests (N = 1,779) to test whether the commonly studied factors had different associations with the different subtypes of vaccination intentions. RESULTS: The analysis showed two distinct factors of vaccination intentions: intentions toward childhood diseases and intentions toward nonchildhood diseases. Additionally, spiritual beliefs, trust in authorities, and belief in conspiracy theories had stronger associations with nonchildhood diseases than with childhood diseases. Fear of needles, prosocial personality, and religious orthodox beliefs did not have different associations with both types of vaccination intentions. CONCLUSIONS: These findings suggest that vaccination intentions is a multidimensional construct and that interventions may benefit from being tailored to the factors relevant for each specific type of vaccine. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Liver glycogen fragility in the presence of hydrogen-bond breakers.

Glycogen, a complex branched glucose polymer, is responsible for sugar storage in blood glucose homeostasis. It comprises small ß particles bound together into composite α particles. In diabetic livers, α particles are fragile, breaking apart into smaller particles in dimethyl sulfoxide, DMSO; they are however stable in glycogen from healthy animals. We postulate that the bond between ß particles in α particles involves hydrogen bonding. Liver-glycogen fragility in normal and db/db mice (an animal model for diabetes) is compared using various hydrogen-bond breakers (DMSO, guanidine and urea) at different temperatures. The results showed different degrees of α-particle disruption. Disrupted glycogen showed changes in the mid-infra-red spectrum that are related to hydrogen bonds. While glycogen α-particles are only fragile under harsh, non-physiological conditions, these results nevertheless imply that the bonding between ß particles in α particles is different in diabetic livers compared to healthy, and is probably associated with hydrogen bonding.

Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction - Results from the EMPULSE trial.

AIM: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium-glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41-49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41-49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. CONCLUSION: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF.

Gaze and attention: Mechanisms underlying the therapeutic effect of optokinetic stimulation in spatial neglect.

Left smooth pursuit eye movement training in response to large-field visual motion (optokinetic stimulation) has become a promising rehabilitation method in left spatial inattention or neglect. The mechanisms underlying the therapeutic effect, however, remain unknown. During optokinetic stimulation, there is an error in visual localisation ahead of the line of sight. This could indicate a change in the brain's estimate of one's own direction of gaze. We hypothesized that optokinetic stimulation changes the brain's estimate of gaze. Because this estimate is critical for coding the locus of attention in the visual space relative to the body and across sensory modalities, its change might underlie the change in spatial attention. Here, we report that in healthy participants optokinetic stimulation causes not only a directional bias in the proprioceptive signal from the extraocular muscles, but also a corresponding shift of the locus of attention. Both changes outlasted the period of stimulation. This result forms a step in investigating a causal link between the adaptation in the sensorimotor gaze signals and the recovery in spatial neglect.

Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis.

Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci1-5. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism6,7; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.

Peptide targeting improves the delivery and therapeutic index of glucocorticoids to treat rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by excessive inflammation in the joints. Glucocorticoid drugs are used clinically to manage RA symptoms, while their dosage and duration need to be tightly controlled due to severe adverse effects. Using dexamethasone (DEX) as a model drug, we explored here whether peptide-guided delivery could increase the safety and therapeutic index of glucocorticoids for RA treatment. Using multiple murine RA models such as collagen-induced arthritis (CIA), we found that CRV, a macrophage-targeting peptide, can selectively home to the inflammatory synovium of RA joints upon intravenous injection. The expression of the CRV receptor, retinoid X receptor beta (RXRB), was also elevated in the inflammatory synovium, likely being the basis of CRV targeting. CRV-conjugated DEX increased the accumulation of DEX in the inflamed synovium but not in healthy organs of CIA mice. Therefore, CRV-DEX demonstrated a stronger efficacy to suppress synovial inflammation and alleviate cartilage/bone destruction. Meanwhile, CRV conjugation reduced immune-related adverse effects of DEX even after a long-term use. Last, we found that RXRB expression was significantly elevated in human patient samples, demonstrating the potential of clinical translation. Taken together, we provide a novel, peptide-targeted strategy to improve the therapeutic efficacy and safety of glucocorticoids for RA treatment.

Associations between 3D-based Left Atrial Volumetric and Blood Flow Parameters in a Single-Site Cohort of the Multi-Ethnic Study of Atherosclerosis.

Purpose To investigate associations between left atrial volume (LAV) and function with impaired three-dimensional hemodynamics from four-dimensional flow MRI. Materials and Methods A subcohort of participants from the Multi-Ethnic Study of Atherosclerosis from Northwestern University underwent prospective 1.5-T cardiac MRI including whole-heart four-dimensional flow and short-axis cine imaging between 2019 and 2020. Four-dimensional flow MRI analysis included manual three-dimensional segmentations of the LA and LA appendage (LAA), which were used to quantify LA and LAA peak velocity and blood stasis (% voxels < 0.1 m/sec). Short-axis cine data were used to delineate LA contours on all cardiac time points, and the resulting three-dimensional-based LAVs were extracted for calculation of LA emptying fractions (LAEFtotal, LAEFactive, LAEFpassive). Stepwise multivariable linear models were calculated for each flow parameter (LA stasis, LA peak velocity, LAA stasis, LAA peak velocity) to determine associations with LAV and LAEF. Results This study included 158 participants (mean age, 73 years ± 7 [SD]; 83 [52.5%] female and 75 [47.4%] male participants). In multivariable models, a 1-unit increase of LAEFtotal was associated with decreased LA stasis (ß coefficient, -0.47%; P < .001), while increased LAEFactive was associated with increased LA peak velocity (ß coefficient, 0.21 cm/sec; P < .001). Furthermore, increased minimum LAV indexed was most associated with impaired LAA flow (higher LAA stasis [ß coefficient, 0.65%; P < .001] and lower LAA peak velocity [ß coefficient, -0.35 cm/sec; P < .001]). Conclusion Higher minimum LAV and reduced LA function were associated with impaired flow characteristics in the LA and LAA. LAV assessment might therefore be a surrogate measure for LA and LAA flow abnormalities. Keywords: Atherosclerosis, Left Atrial Volume, Left Atrial Blood Flow, 4D Flow MRI Supplemental material is available for this article. © RSNA, 2024.

Contemporary approach to cardiogenic shock care: a state-of-the-art review.

Cardiogenic shock (CS) is a time-sensitive and hemodynamically complex syndrome with a broad spectrum of etiologies and clinical presentations. Despite contemporary therapies, CS continues to maintain high morbidity and mortality ranging from 35 to 50%. More recently, burgeoning observational research in this field aimed at enhancing the early recognition and characterization of the shock state through standardized team-based protocols, comprehensive hemodynamic profiling, and tailored and selective utilization of temporary mechanical circulatory support devices has been associated with improved outcomes. In this narrative review, we discuss the pathophysiology of CS, novel phenotypes, evolving definitions and staging systems, currently available pharmacologic and device-based therapies, standardized, team-based management protocols, and regionalized systems-of-care aimed at improving shock outcomes. We also explore opportunities for fertile investigation through randomized and non-randomized studies to address the prevailing knowledge gaps that will be critical to improving long-term outcomes.

Development and Evaluation of I-PASS-to-PICU: A Standard Electronic Template to Improve Referral Communication for Interfacility Transfers to the Pediatric ICU.

BACKGROUND: Miscommunication during interfacility handoffs to a higher level of care can harm critically ill children. Adapting evidence-based handoff interventions to interfacility referral communication may prevent adverse events. The objective of this project was to develop and evaluate a standard electronic referral template (I-PASS-to-PICU) to improve communication for interfacility pediatric ICU (PICU) transfers. METHODS: I-PASS-to-PICU was iteratively developed in a single PICU. A core PICU stakeholder group collaboratively designed an electronic health record (EHR)-supported clinical note template by adapting elements from I-PASS, an evidence-based handoff program, to support information exchange between referring clinicians and receiving PICU physicians. I-PASS-to-PICU is a receiver-driven tool used by PICU physicians to guide verbal communication and electronic documentation during PICU transfer calls. The template underwent three cycles of iterative evaluation and redesign informed by individual and group interviews of multidisciplinary PICU staff, usability testing using simulated and actual referral calls, and debriefing with PICU physicians. RESULTS: Individual and group interviews with 21 PICU staff members revealed that relevant, accurate, and concise information was needed for adequate admission preparedness. Time constraints and secondhand information transmission were identified as barriers. Usability testing with six receiving PICU physicians using simulated and actual calls revealed good usability on the validated System Usability Scale (SUS), with a mean score of 77.5 (standard deviation 10.9). Fellows indicated that most fields were relevant and that the template was feasible to use. CONCLUSION: I-PASS-to-PICU was technically feasible, usable, and relevant. The authors plan to further evaluate its effectiveness in improving information exchange during real-time PICU practice.