Compression drives diverse transcriptomic and phenotypic adaptations in melanoma.

Physical forces are prominent during tumor progression. However, it is still unclear how they impact and drive the diverse phenotypes found in cancer. Here, we apply an integrative approach to investigate the impact of compression on melanoma cells. We apply bioinformatics to screen for the most significant compression-induced transcriptomic changes and investigate phenotypic responses. We show that compression-induced transcriptomic changes are associated with both improvement and worsening of patient prognoses. Phenotypically, volumetric compression inhibits cell proliferation and cell migration. It also induces organelle stress and intracellular oxidative stress and increases pigmentation in malignant melanoma cells and normal human melanocytes. Finally, cells that have undergone compression become more resistant to cisplatin treatment. Our findings indicate that volumetric compression is a double-edged sword for melanoma progression and drives tumor evolution.

Biophysical informatics reveals distinctive phenotypic signatures and functional diversity of single-cell lineages.

MOTIVATION: In this work, we present an analytical method for quantifying both single-cell morphologies and cell network topologies of tumor cell populations and use it to predict 3D cell behavior. RESULTS: We utilized a supervised deep learning approach to perform instance segmentation on label-free live cell images across a wide range of cell densities. We measured cell shape properties and characterized network topologies for 136 single-cell clones derived from the YUMM1.7 and YUMMER1.7 mouse melanoma cell lines. Using an unsupervised clustering algorithm, we identified six distinct morphological subclasses. We further observed differences in tumor growth and invasion dynamics across subclasses in an in vitro 3D spheroid model. Compared to existing methods for quantifying 2D or 3D phenotype, our analytical method requires less time, needs no specialized equipment and is capable of much higher throughput, making it ideal for applications such as high-throughput drug screening and clinical diagnosis. AVAILABILITY AND IMPLEMENTATION: https://github.com/trevor-chan/Melanoma_NetworkMorphology. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

IL-23 induces CLEC5A+ IL-17A+ neutrophils and elicit skin inflammation associated with psoriatic arthritis.

IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23RGFP reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1+CD11b+Ly6G+ population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis. Genetic ablation of MDL-1, a major PU.1 transcriptional target during myeloid differentiation exclusively expressed in myeloid cells, completely prevents IL-23-pathology. Moreover, we show that IL-23-induced myeloid subsets are also capable of producing IL-17A and IL-23R+MDL1+ cells are present in the involved skin of psoriasis patients and gene expression correlations between IL-23 and MDL-1 have been validated in multiple patient cohorts. Collectively, our data demonstrate a novel role of IL-23 in MDL-1-myelopoiesis that is responsible for skin inflammation and related pathologies. Our data open a new avenue of investigations regarding the role of IL-23 in the activation of myeloid immunoreceptors and their role in autoimmunity.

High speed optical phased array using high contrast grating all-pass filters.

We report a high speed 8x8 optical phased array using tunable 1550 nm all-pass filters with ultrathin high contrast gratings (HCGs) as the microelectromechanical-actuated top reflectors. The all-pass filter design enables a highly efficient phase tuning (1.7 π) with a small actuation voltage (10 V) and actuation displacement of the HCG (50 nm). The microelectromechanical HCG structure facilitates a high phase tuning speed >0.5 MHz. Beam steering is experimentally demonstrated with the optical phased array.

Use of abdominal thrusts is associated with improved rates of successful emesis induction in dogs.

OBJECTIVE: To evaluate the effect of abdominal thrusts as a synergistic procedure to IV apomorphine administration on the occurrence and rate of onset of successful induction of emesis in dogs. ANIMALS: 31 client-owned dogs. METHODS: Dogs in which induction of emesis via IV apomorphine was prescribed by the attending clinician were prospectively randomized to either receive abdominal thrusts performed by a nurse or clinician or to have no physical interventions performed following IV apomorphine administration. Data collected included signalment, weight, reason for emesis, time from suspected ingestion to presentation, time from the dog's last meal to presentation, dose of apomorphine administered in milligrams, and time from apomorphine administration to emesis. RESULTS: Emesis induction was successful in 14 of 14 (100%) of the dogs in the abdominal thrust group and 13 of 17 (76.5%) in the control group (P = .02). In dogs with successful emesis, median time to emesis was 90.5 seconds (range, 36 to 348 seconds) in the abdominal thrust group and 106 seconds (range, 37 to 360 seconds) in the control group (P = .29). CLINICAL RELEVANCE: Abdominal thrusts were associated with an increased frequency of successful emesis in dogs following IV apomorphine, but did not shorten the rate of onset of emesis in dogs that vomited. Application of abdominal thrusts may be beneficial in dogs in which emesis is indicated and that do not have a clear contraindication.

Behavioural 'nudging' interventions to reduce low-value care for low back pain in the emergency department (NUDG-ED): protocol for a 2×2 factorial, before-after, cluster randomised trial.

INTRODUCTION: Opioids and imaging are considered low-value care for most people with low back pain. Yet around one in three people presenting to the emergency department (ED) will receive imaging, and two in three will receive an opioid. NUDG-ED aims to determine the effectiveness of two different behavioural 'nudge' interventions on low-value care for ED patients with low back pain. METHODS AND ANALYSIS: NUDG-ED is a 2×2 factorial, open-label, before-after, cluster randomised controlled trial. The trial includes 8 ED sites in Sydney, Australia. Participants will be ED clinicians who manage back pain, and patients who are 18 years or over presenting to ED with musculoskeletal back pain. EDs will be randomly assigned to receive (i) patient nudges, (ii) clinician nudges, (iii) both interventions or (iv) no nudge control. The primary outcome will be the proportion of encounters in ED for musculoskeletal back pain where a person received a non-indicated lumbar imaging test, an opioid at discharge or both. We will require 2416 encounters over a 9-month study period (3-month before period and 6-month after period) to detect an absolute difference of 10% in use of low-value care due to either nudge, with 80% power, alpha set at 0.05 and assuming an intra-class correlation coefficient of 0.10, and an intraperiod correlation of 0.09. Patient-reported outcome measures will be collected in a subsample of patients (n≥456) 1 week after their initial ED visit. To estimate effects, we will use a multilevel regression model, with a random effect for cluster and patient, a fixed effect indicating the group assignment of each cluster and a fixed effect of time. ETHICS AND DISSEMINATION: This study has ethical approval from Southwestern Sydney Local Health District Human Research Ethics Committee (2023/ETH00472). We will disseminate the results of this trial via media, presenting at conferences and scientific publications. TRIAL REGISTRATION NUMBER: ACTRN12623001000695.

A Hybrid Auricular Framework of Autologous Rib Cartilage and a Porous Polyethylene Implant for Reconstruction of Congenital Microtia: A Modification of Nagata's Technique.

Background: An implant (porous polyethylene) is an alternative to rib cartilage for microtia reconstruction but carries a risk of extrusion. Objective: To evaluate the outcome of a hybrid framework of implant with rib cartilage for microtia reconstruction. Methods: Patients who underwent Nagata's technique for microtia reconstruction were reviewed for complications and aesthetic score. In stage 1, a rib cartilage framework or a hybrid framework of implant with rib cartilage was used. In stage 2, the framework was elevated and supported by an implant for projection. Postoperative outcomes were reported for both groups. Results: Forty-four ears of 40 patients underwent surgery. Eleven ears received a rib auricular framework and 33 ears a hybrid auricular framework. The mean postoperative follow-up for the rib and hybrid groups was 76.3 and 43.1 months, respectively. No supporting postauricular implant extruded, whereas stainless-steel wires extruded in seven ears (15.9%). Five (15.2%) hybrid frameworks were removed due to infection or extrusion. Mean operating time was 2 h shorter in the hybrid group. Aesthetic outcomes were similar for both groups. Conclusion: A hybrid framework of rib and implant that requires less harvested cartilage is feasible for microtia reconstruction, but caution should be used due to its higher explantation rate.

Optical beamsteering using an 8 × 8 MEMS phased array with closed-loop interferometric phase control.

We present a high-speed optical beamsteering system based on an 8x8 MEMS phased array. The system incorporates an in situ interferometer that provides a real-time, dynamic measure of the phase of each mirror in the array during beamsteering. A closed-loop phase-control algorithm results in <π/100 mirror phase accuracy and far field beam steering is shown. Stroboscopic measurement capabilities are demonstrated which allow us to show feedforward control to eliminate micromirror ringing.

Optical phased array using high contrast gratings for two dimensional beamforming and beamsteering.

We have developed a microelectromechanical system (MEMS) optical phased array incorporating a high-index-contrast subwavelength grating (HCG) for beamforming and beamsteering in a range of ± 1.26° × 1.26°. Our approach needs only a thin single-layer HCG made of silicon, considerably improving its speed thanks to the low mass, and is suitable for high optical power applications. The measured resonant frequency of HCG is 0.32 MHz.

Validity of criteria for dementia in older people with intellectual disability.

OBJECTIVE: Valid definitions of dementia should discriminate dementia from other forms of cognitive impairment such as intellectual disability (ID). We aimed to evaluate the usefulness of criteria for dementia and mild cognitive impairment (MCI) in ID, including predictive validity, and inter-rater reliability. METHOD: We assessed 222 participants in a survey of older adults with ID without Down syndrome at two time points for dementia (T1 and T2). Mean follow-up period was 2.9 years. Dementia diagnoses were made according to International Classification of Diseases, Tenth Revision, Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), Diagnostic criteria for psychiatric disorders for use with adults with learning disabilities (DC-LD) criteria. At follow-up (T2), raters were blind to initial diagnosis. Predictive validity was determined by comparing odds ratios (ORs) of death, or of having a "poor outcome" (i.e., either dying or being diagnosed with dementia at T2). RESULTS: All dementia criteria showed substantial inter-rater reliability (κ > 0.68) and high specificity (~95%). Dementia cases at T1 were more likely to have died at T2 than those with no dementia (33.3% versus 14.9%; OR: 2.85; 95% confidence interval (95% CI): 1.12-7.22) and to have a "poor outcome" (77.8% versus 27.6%; OR: 9.18; 95% CI: 3.43-24.53). At least two dementia cases at T1 were false positives. Those with "MCI" at T1 were similar to "no dementia" cases in terms of poor outcomes at T2. CONCLUSION: Dementia diagnostic criteria show substantial reliability and satisfactory validity in ID. The diagnoses were, however, less stable than in the general population and some caution is advisable in those with more severe ID or additional sensory disability. MCI definitions require further consideration in the ID population.

A Super-Resolution Diffusion Model for Recovering Bone Microstructure from CT Images.

Purpose: To use a diffusion-based deep learning model to recover bone microstructure from low-resolution images of the proximal femur, a common site of traumatic osteoporotic fractures. Materials and Methods: Training and testing data in this retrospective study consisted of high-resolution cadaveric micro-CT scans (n = 26), which served as ground truth. The images were downsampled prior to use for model training. The model was used to increase spatial resolution in these low-resolution images threefold, from 0.72 mm to 0.24 mm, sufficient to visualize bone microstructure. Model performance was validated using microstructural metrics and finite element simulation-derived stiffness of trabecular regions. Performance was also evaluated across a handful of image quality assessment metrics. Correlations between model performance and ground truth were assessed using intraclass correlation coefficients (ICCs) and Pearson correlation coefficients. Results: Compared with popular deep learning baselines, the proposed model exhibited greater accuracy (mean ICC of proposed model, 0.92 vs ICC of next best method, 0.83) and lower bias (mean difference in means, 3.80% vs 10.00%, respectively) across the physiologic metrics. Two gradient-based image quality metrics strongly correlated with accuracy across structural and mechanical criteria (r > 0.89). Conclusion: The proposed method may enable accurate measurements of bone structure and strength with a radiation dose on par with current clinical imaging protocols, improving the viability of clinical CT for assessing bone health.Keywords: CT, Image Postprocessing, Skeletal-Appendicular, Long Bones, Radiation Effects, Quantification, Prognosis, Semisupervised Learning Online supplemental material is available for this article. © RSNA, 2023.

Bed tilt and ramp positions are associated with increased first-pass success of adult endotracheal intubation in the emergency department: A registry study.

OBJECTIVE: Successful endotracheal intubation in the ED requires optimum body positioning. In patients with obesity, the ramp position was suggested to achieve better intubating conditions. However, limited data are available on the airway management practices for patients with obesity in Australasian EDs. The aim of this study was to identify current patient positioning practices during endotracheal intubation and its association with first-pass success (FPS) at intubation and adverse event (AE) rates in obese and non-obese populations. METHODS: Prospectively collected data from the Australia and New Zealand ED Airway Registry (ANZEDAR) between 2012 and 2019 were analysed. Patients were categorised into two groups according to their weight: <100 kg (non-obese) or ≥100 kg (obese). Four position categories were investigated; supine, pillow or occipital pad, bed tilt and ramp or head-up with relation to FPS and complication rate using logistic regression modelling. RESULTS: A total of 3708 intubations from 43 EDs were included. Overall, the non-obese cohort had a greater FPS rate (85.9%) compared to the obese group (77.0%). The bed tilt position had the highest FPS rate (87.2%), whereas the supine position had the lowest (83.0%). AE rates were highest in the ramp position (31.2%) compared to all other positions (23.8%). Regression analysis showed ramp, or bed tilt positions and a consultant-level intubator were associated with higher FPS. Obesity, in addition to other factors, was independently associated with lower FPS. CONCLUSION: Obesity was associated with lower FPS, which could be improved through performing a bed tilt or ramp positioning.

Automated, calibration-free quantification of cortical bone porosity and geometry in postmenopausal osteoporosis from ultrashort echo time MRI and deep learning.

BACKGROUND: Assessment of cortical bone porosity and geometry by imaging in vivo can provide useful information about bone quality that is independent of bone mineral density (BMD). Ultrashort echo time (UTE) MRI techniques of measuring cortical bone porosity and geometry have been extensively validated in preclinical studies and have recently been shown to detect impaired bone quality in vivo in patients with osteoporosis. However, these techniques rely on laborious image segmentation, which is clinically impractical. Additionally, UTE MRI porosity techniques typically require long scan times or external calibration samples and elaborate physics processing, which limit their translatability. To this end, the UTE MRI-derived Suppression Ratio has been proposed as a simple-to-calculate, reference-free biomarker of porosity which can be acquired in clinically feasible acquisition times. PURPOSE: To explore whether a deep learning method can automate cortical bone segmentation and the corresponding analysis of cortical bone imaging biomarkers, and to investigate the Suppression Ratio as a fast, simple, and reference-free biomarker of cortical bone porosity. METHODS: In this retrospective study, a deep learning 2D U-Net was trained to segment the tibial cortex from 48 individual image sets comprised of 46 slices each, corresponding to 2208 training slices. Network performance was validated through an external test dataset comprised of 28 scans from 3 groups: (1) 10 healthy, young participants, (2) 9 postmenopausal, non-osteoporotic women, and (3) 9 postmenopausal, osteoporotic women. The accuracy of automated porosity and geometry quantifications were assessed with the coefficient of determination and the intraclass correlation coefficient (ICC). Furthermore, automated MRI biomarkers were compared between groups and to dual energy X-ray absorptiometry (DXA)- and peripheral quantitative CT (pQCT)-derived BMD. Additionally, the Suppression Ratio was compared to UTE porosity techniques based on calibration samples. RESULTS: The deep learning model provided accurate labeling (Dice score 0.93, intersection-over-union 0.88) and similar results to manual segmentation in quantifying cortical porosity (R2 ≥ 0.97, ICC ≥ 0.98) and geometry (R2 ≥ 0.82, ICC ≥ 0.75) parameters in vivo. Furthermore, the Suppression Ratio was validated compared to established porosity protocols (R2 ≥ 0.78). Automated parameters detected age- and osteoporosis-related impairments in cortical bone porosity (P ≤ .002) and geometry (P values ranging from <0.001 to 0.08). Finally, automated porosity markers showed strong, inverse Pearson's correlations with BMD measured by pQCT (|R| ≥ 0.88) and DXA (|R| ≥ 0.76) in postmenopausal women, confirming that lower mineral density corresponds to greater porosity. CONCLUSION: This study demonstrated feasibility of a simple, automated, and ionizing-radiation-free protocol for quantifying cortical bone porosity and geometry in vivo from UTE MRI and deep learning.

Most accurate definition of a high femoral artery puncture: aiming to better predict retroperitoneal hematoma in percutaneous coronary intervention.

BACKGROUND: Retroperitoneal hematoma (RPH) increases morbidity and mortality in percutaneous coronary intervention (PCI). High femoral arteriotomy is an independent predictor of RPH, but the optimal angiographic criterion for defining a high puncture is unknown. METHODS: We retrospectively identified 557 consecutive PCI cases with femoral angiograms. Arteriotomy sites were categorized as high based on three angiographic criteria: at or above the proximal third of the femoral head (criterion A), at or above the most inferior border of the inferior epigastric artery (criterion B), and at or above the origin of the inferior epigastric artery (criterion C). Cases of RPH were then identified. RESULTS: Of the 557 PCI patients, 26 had a high femoral arteriotomy by criterion A, 17 by criterion B, and 6 by criterion C. Among these patients with a high arteriotomy, RPH occurred in four with criterion A, in three with criterion B, and in one with criterion C. Of the three criteria, criterion A most strongly correlated with RPH (odds ratio [OR] 96, 95% confidence interval [CI] 10.3-898.4; p < 0.0001) compared with criterion B (OR 58, 95% CI 8.9 to 372.6; p < 0.0001) or C (OR 27, 95% CI 2.6 to 290.1; p = 0.053). All criteria had high specificity (A, 96%; B, 97%; C, 99%), but the sensitivity was higher with criterion A (80%) than criterion B (60%) or C (20%), and statistically, the use of criterion A led to the most accurate risk-stratification for RPH (A, κ = 0.79; B, κ = 0.59; C, κ = 0.19). CONCLUSIONS: Among the three common definitions of high arteriotomy, femoral artery puncture at or above the proximal third of the femoral head is the landmark that most accurately risk stratifies PCI patients for development of RPH.

Audit lead selection and yield prediction from historical tax data using artificial neural networks.

Tax audits are a crucial process adopted in all tax departments to ensure tax compliance and fairness. Traditionally, tax audit leads have been selected based on empirical rules and randomization methods, which are not adaptive, may miss major cases and can introduce bias. Here, we present an audit lead tool based on artificial neural networks that have been trained and evaluated on an integrated dataset of 93,413 unique tax records from 8,647 restaurant businesses over 10 years in the Northern California, provided by the California Department of Tax and Fee Administration (CDTFA). The tool achieved a 40.1% precision and 58.7% recall (F1-score of 0.42) on classifying positive audit leads, and the corresponding regressor provided estimated audit gains (MAE of $155,490). Finally, we evaluated the statistical significance of various empirical rules for use in lead selection, with two out of five being supported by the data. This work demonstrates how data can be leveraged for creating evidence-based models of audit selection and validating empirical hypotheses, resulting in higher audit yields and more fair audit selection processes.

A microfluidic-informatics assay for quantitative physical occlusion measurement in sickle cell disease.

Sickle cell disease (SCD) is a genetic condition that causes abnormalities in hemoglobin mechanics. Those affected are at high risk of vaso-occlusive crisis (VOC), which can induce life-threatening symptoms. The development of measurements related to vaso-occlusion facilitates the diagnosis of the patient's disease state. To complement existing readouts, we design a microfluidic-informatics analytical system with varied confined geometries for the quantification of sickle cell disease occlusion. We detect an increase in physical occlusion events in the most severe hemoglobin SS group. We use bioinformatics and modeling to quantify the in vitro disease severity score (DSS) of individual patients. We also show the potential effect of hydration, clinically recommended for crisis management, on reducing the disease severity of high-risk patients. Overall, we demonstrate the device as an easy-to-use assay for quick occlusion information extraction with a simple setup and minimal additional instruments. We show the device can provide physical readouts distinct from clinical data. We also show the device sensitivity in separate samples from patients with different disease severity. Finally, we demonstrate the system as a potential platform for testing the effectiveness of therapeutic strategies (e.g. hydration) on reducing sickle cell disease severity.

A molecular MRI probe to detect treatment of cardiac apoptosis in vivo.

Cell death by apoptosis is critical in myocardial diseases, and noninvasive detection of early, reversible apoptosis might be useful clinically. Exogenous Annexin-V (ANX) protein binds membrane phosphatidylserine, which is externalized in early apoptosis. A molecular MRI probe was constructed with superparamagnetic iron oxide (SPIO) conjugated to recombinant human ANX (ANX-SPIO). Apoptosis was induced with doxorubicin, a cardiotoxic cancer drug, in culture in neonatal rat ventricular myocytes, cardiac fibroblasts, and mesenchymal stem cells, and in vivo in the mouse heart. ANX-SPIO was validated using T2*-weighted 3T MRI. ANX-SPIO produced T2* signal loss, reflecting iron content, that correlated highly with independent apoptosis markers; bound with high affinity to apoptotic myocytes by competition assay (Ki 69 nM); detected apoptosis in culture much earlier than did TUNEL stain; and revealed fibroblast resistance to apoptosis. With apoptosis in vivo, ANX-SPIO produced diffuse myocardial T2* signal loss that correlated with increased iron stain and caspase activity. Treatment with an alpha-1-adrenergic agonist in vivo reversed apoptosis and eliminated the ANX-SPIO MRI signal. It is concluded that cardiac MRI of ANX-SPIO detects early, nonischemic cardiac apoptosis in culture and in vivo, and can identify reversibly injured cardiac cells in diseased hearts, when treatment is still possible.

Morphodynamic signatures of MDA-MB-231 single cells and cell doublets undergoing invasion in confined microenvironments.

Cancer cell metastasis is a major factor in cancer-related mortality. During the process of metastasis, cancer cells exhibit migratory phenotypes and invade through pores in the dense extracellular matrix. However, the characterization of morphological and subcellular features of cells in similar migratory phenotypes and the effects of geometric confinement on cell morphodynamics are not well understood. Here, we investigate the phenotypes of highly aggressive MDA-MB-231 cells in single cell and cell doublet (an initial and simplified collective state) forms in confined microenvironments. We group phenotypically similar single cells and cell doublets and characterize related morphological and subcellular features. We further detect two distinct migratory phenotypes, fluctuating and non-fluctuating, within the fast migrating single cell group. In addition, we demonstrate an increase in the number of protrusions formed at the leading edge of cells after invasion through geometric confinement. Finally, we track the short and long term effects of varied degrees of confinement on protrusion formation. Overall, our findings elucidate the underlying morphological and subcellular features associated with different single cell and cell doublet phenotypes and the impact of invasion through confined geometry on cell behavior.

2-Dimensional beamsteering using dispersive deflectors and wavelength tuning.

We introduce a 2D beamscanner which is controlled by wavelength tuning. Two passive dispersive devices are aligned orthogonally to deflect the optical beam in two dimensions. We provide a proof of principle demonstration by combining an arrayed waveguide grating with a free space optical grating and using various input sources to characterize the beamscanner. This achieved a discrete 10.3 degrees by 11 degrees output field of view with attainable angles existing on an 8 by 6 grid of directions. The entire range was reached by scanning over a 40 nm wavelength range. We also analyze an improved system combining a virtually imaged phased array with a diffraction grating. This device is much more compact and produces a continuous output scan in one direction while being discrete in the other.

Integrated diffractive shearing interferometry for adaptive wavefront sensing.

We present theory, design, and preliminary experimental studies for a compact wavefront sensor based on lateral shearing interferometry using a binary phase grating, image sensor, and Fourier-based processing. The integrated system places a diffractive element directly onto an image sensor to generate interference fringes within overlapping diffraction orders. The shearing ratio and the interferogram signal-to-noise ratio directly affect the reconstruction accuracy of wavefronts with differing spatial variations. Optimal shearing parameters associated with the autocorrelation of the input encourage placing a spatial light modulator as the diffractive element allowing adaptive wavefront sensing. Experimental results from a fixed-grating system are presented as well as requirements for next-generation adaptive systems.