Assessing the prognostic utility of clinical and radiomic features for COVID-19 patients admitted to ICU: challenges and lessons learned.

Severe cases of COVID-19 often necessitate escalation to the Intensive Care Unit (ICU), where patients may face grave outcomes, including mortality. Chest X-rays play a crucial role in the diagnostic process for evaluating COVID-19 patients. Our collaborative efforts with Michigan Medicine in monitoring patient outcomes within the ICU have motivated us to investigate the potential advantages of incorporating clinical information and chest X-ray images for predicting patient outcomes. We propose an analytical workflow to address challenges such as the absence of standardized approaches for image pre-processing and data utilization. We then propose an ensemble learning approach designed to maximize the information derived from multiple prediction algorithms. This entails optimizing the weights within the ensemble and considering the common variability present in individual risk scores. Our simulations demonstrate the superior performance of this weighted ensemble averaging approach across various scenarios. We apply this refined ensemble methodology to analyze post-ICU COVID-19 mortality, an occurrence observed in 21% of COVID-19 patients admitted to the ICU at Michigan Medicine. Our findings reveal substantial performance improvement when incorporating imaging data compared to models trained solely on clinical risk factors. Furthermore, the addition of radiomic features yields even larger enhancements, particularly among older and more medically compromised patients. These results may carry implications for enhancing patient outcomes in similar clinical contexts.

Bayesian Inference for High Dimensional Cox Models with Gaussian and Diffused-Gamma Priors: A Case Study of Mortality in COVID-19 Patients Admitted to the ICU.

Bayesian approaches have been utilized to address the challenge of variable selection and statistical inference in high-dimensional survival analysis. However, the discontinuity of the ℓ0-norm prior, including the useful spike-and-slab prior, may lead to computational and implementation challenges, potentially limiting the widespread use of Bayesian methods. The Gaussian and diffused-gamma (GD) prior has emerged as a promising alternative due to its continuous-and-differentiable ℓ0-norm approximation and computational efficiency in generalized linear models. In this paper, we extend the GD prior to semi-parametric Cox models by proposing a rank-based Bayesian inference procedure with the Cox partial likelihood. We develop a computationally efficient algorithm based on the iterative conditional mode (ICM) and Markov chain Monte Carlo methods for posterior inference. Our simulations demonstrate the effectiveness of the proposed method, and we apply it to an electronic health record dataset to identify risk factors associated with COVID-19 mortality in ICU patients at a regional medical center.

What evidence is needed to inform postoperative opioid consumption guidelines? A cohort study of the Michigan Surgical Quality Collaborative.

INTRODUCTION: To balance adequate pain management while minimizing opioid-related harms after surgery, opioid prescribing guidelines rely on patient-reported use after surgery. However, it is unclear how many patients are required to develop precise guidelines. We aimed to compare patterns of use, required sample size, and the precision for patient-reported opioid consumption after common surgical procedures. METHODS: We analyzed procedure-specific 30-day opioid consumption data reported after discharge from 15 common surgical procedures between January 2018 and May 2019 across 65 hospitals in the Michigan Surgical Quality Collaborative. We calculated proportions of patients using no pills and the estimated number of pills meeting most patients' needs, defined as the 75th percentile of consumption. We compared several methods to model consumption patterns. Using the best method (Tweedie), we calculated sample sizes required to identify opioid consumption within a 5-pill interval and estimates of pills to meet most patients' needs by calculating the width of 95% CIs. RESULTS: In a cohort of 10,688 patients, many patients did not consume any opioids after all types of procedures (range 20%-40%). Most patients' needs were met with 4 pills (thyroidectomy) to 13 pills (abdominal hysterectomy). Sample sizes required to estimate opioid consumption within a 5-pill wide 95% CI ranged from 48 for laparoscopic appendectomy to 188 for open colectomy. The 95% CI width for estimates ranged from 0.7 pills for laparoscopic cholecystectomy to 7.0 pills for ileostomy/colostomy. CONCLUSIONS: This study demonstrates that profiles of opioid consumption share more similarities than differences for certain surgical procedures. Future investigations on patient-reported consumption are required for procedures not currently included in prescribing guidelines to ensure surgeons and perioperative providers can appropriately tailor recommendations to the postoperative needs of patients.

Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement.

Cell migration through confining three dimensional (3D) topographies can lead to loss of nuclear envelope integrity, DNA damage, and genomic instability. Despite these detrimental phenomena, cells transiently exposed to confinement do not usually die. Whether this is also true for cells subjected to long-term confinement remains unclear at present. To investigate this, photopatterning and microfluidics are employed to fabricate a high-throughput device that circumvents limitations of previous cell confinement models and enables prolonged culture of single cells in microchannels with physiologically relevant length scales. The results of this study show that continuous exposure to tight confinement can trigger frequent nuclear envelope rupture events, which in turn promote P53 activation and cell apoptosis. Migrating cells eventually adapt to confinement and evade cell death by downregulating YAP activity. Reduced YAP activity, which is the consequence of confinement-induced YAP1/2 translocation to the cytoplasm, suppresses the incidence of nuclear envelope rupture and abolishes P53-mediated cell death. Cumulatively, this work establishes advanced, high-throughput biomimetic models for better understanding cell behavior in health and disease, and underscores the critical role of topographical cues and mechanotransduction pathways in the regulation of cell life and death.

Hydrogels to Recapture Extracellular Matrix Cues That Regulate Vascularization.

The ECM (extracellular matrix) is a 3-dimensional network that supports cellular responses and maintains structural tissue integrity in healthy and pathological conditions. The interactions between ECM and cells trigger signaling cascades that lead to phenotypic changes and structural and compositional turnover of the ECM, which in turn regulates vascular cell behavior. Hydrogel biomaterials are a powerful platform for basic and translational studies and clinical applications due to their high swelling capacity and exceptional versatility in compositions and properties. This review highlights recent developments and uses of engineered natural hydrogel platforms that mimic the ECM and present defined biochemical and mechanical cues for vascularization. Specifically, we focus on modulating vascular cell stimulation and cell-ECM/cell-cell interactions in the microvasculature that are the established biomimetic microenvironment.

Toddler-teacher interaction and teachers' sensitivity as predictors of toddler's development during COVID-19: Stability or change over time.

This study examined the stability and change patterns among toddlers' interactions with their teachers, teachers' sensitivity, and toddlers' development during the COVID-19 pandemic and the three plausible paths were tested to identify which of the study variables affected the development of toddlers in subsequent periods over time. The subjects of this study were 63 toddlers and 6 head teachers who attended a subsidized child care center, located in Kyunggi province, Korea. In order to carry out the research objectives, a non-experimental survey research design was undertaken, and the qualitative data was obtained via on-site observations by trained researchers. With regard to continuity and change patterns among the study variables toddlers who had been actively involved in initiating their verbal interactions with teachers showed more verbal interactions with their teachers even after 4 months passed. Also, it was found that the early (T1) social disposition of toddlers and the behavioral interaction that toddlers had initiated with teachers revealed a significant effect, supporting each of the three models, which are simultaneous, cumulative, and complex paths. The main results of this research support the contention that the interaction patterns vary by contexts of subject, time, and history, indicating that it would be useful to understand new competencies required for teachers within the context of the multi-faceted ramifications of the pandemic on toddler development.

Use of machine learning to assess the prognostic utility of radiomic features for in-hospital COVID-19 mortality.

As portable chest X-rays are an efficient means of triaging emergent cases, their use has raised the question as to whether imaging carries additional prognostic utility for survival among patients with COVID-19. This study assessed the importance of known risk factors on in-hospital mortality and investigated the predictive utility of radiomic texture features using various machine learning approaches. We detected incremental improvements in survival prognostication utilizing texture features derived from emergent chest X-rays, particularly among older patients or those with a higher comorbidity burden. Important features included age, oxygen saturation, blood pressure, and certain comorbid conditions, as well as image features related to the intensity and variability of pixel distribution. Thus, widely available chest X-rays, in conjunction with clinical information, may be predictive of survival outcomes of patients with COVID-19, especially older, sicker patients, and can aid in disease management by providing additional information.

Predictors of Progression of Tricuspid Regurgitation in Patients with Persistent Atrial Fibrillation.

Previous studies have shown that tricuspid regurgitation (TR) can be developed in patients with atrial fibrillation (AF) due to annular dilatation. This study aimed to investigate the incidence and predictors of the progression of TR in patients with persistent AF. A total of 397 patients (66.9±11.4 years, 247 men; 62.2%) with persistent AF were enrolled between 2006 and 2016 in a tertiary hospital, and 287 eligible patients with follow-up echocardiography were analyzed. They were divided into two groups according to TR progression (progression group [n=68, 70.1±10.7 years, 48.5% men] vs. non-progression group [n=219, 66.0±11.3 years, 64.8% men]). Among 287 patients in the analysis, 68 had worsening TR severity (23.7%). Patients in the TR progression group were older and more likely to be female. Patients with left ventricular ejection fraction <50% were less frequent in the progression group than those in the non-progression group (7.4% vs. 19.6%, p=0.018). Patients with mitral valve disease were more frequent in the progression group. Multivariate analysis with COX regression demonstrated independent predictors of TR progression, including left atrial (LA) diameter >54 mm (HR 4.85, 95%CI 2.23-10.57, p<0.001), E/e' (HR 1.05, 95%CI 1.01-1.10, p=0.027), and no use of antiarrhythmic agents (HR 2.20, 95%CI 1.03-4.72, p=0.041). In patients with persistent AF, worsening TR was not uncommon. The independent predictors of TR progression turned out to be greater LA diameter, higher E/e', and no use of antiarrhythmic agents.

Matrix Adhesiveness Regulates Myofibroblast Differentiation from Vocal Fold Fibroblasts in a Bio-orthogonally Cross-linked Hydrogel.

Repeated mechanical and chemical insults cause an irreversible alteration of extracellular matrix (ECM) composition and properties, giving rise to vocal fold scarring that is refractory to treatment. Although it is well known that fibroblast activation to myofibroblast is the key to the development of the pathology, the lack of a physiologically relevant in vitro model of vocal folds impedes mechanistic investigations on how ECM cues promote myofibroblast differentiation. Herein, we describe a bio-orthogonally cross-linked hydrogel platform that recapitulates the alteration of matrix adhesiveness due to enhanced fibronectin deposition when vocal fold wound healing is initiated. The synthetic ECM (sECM) was established via the cycloaddition reaction of tetrazine (Tz) with slow (norbornene, Nb)- and fast (trans-cyclooctene, TCO)-reacting dienophiles. The relatively slow Tz-Nb ligation allowed the establishment of the covalent hydrogel network for 3D cell encapsulation, while the rapid and efficient Tz-TCO reaction enabled precise conjugation of the cell-adhesive RGDSP peptide in the hydrogel network. To mimic the dynamic changes of ECM composition during wound healing, RGDSP was conjugated to cell-laden hydrogel constructs via a diffusion-controlled bioorthognal ligation method 3 days post encapsulation. At a low RGDSP concentration (0.2 mM), fibroblasts residing in the hydrogel remained quiescent when maintained in transforming growth factor beta 1 (TGF-ß1)-conditioned media. However, at a high concentration (2 mM), RGDSP potentiated TGF-ß1-induced myofibroblast differentiation, as evidenced by the formation of an actin cytoskeleton network, including F-actin and alpha-smooth muscle actin. The RGDSP-driven fibroblast activation to myofibroblast was accompanied with an increase in the expression of wound healing-related genes, the secretion of profibrotic cytokines, and matrix contraction required for tissue remodeling. This work represents the first step toward the establishment of a 3D hydrogel-based cellular model for studying myofibroblast differentiation in a defined niche associated with vocal fold scarring.

Tunable Synthesis of Hydrogel Microfibers via Interfacial Tetrazine Ligation.

Crosslinked, degradable, and cell-adhesive hydrogel microfibers were synthesized via interfacial polymerization employing tetrazine ligation, an exceptionally fast bioorthogonal reaction between strained trans-cyclooctene (TCO) and s-tetrazine (Tz). A hydrophobic trisTCO crosslinker and homo-difunctional poly(ethylene glycol) (PEG)-based macromers with the tetrazine group conjugated to PEG via a stable carbamate (PEG-bisTz1) bond or a labile hydrazone (PEG-bisTz2) linkage were synthesized. After laying an ethyl acetate solution of trisTCO over an aqueous solution of bisTz macromers, mechanically robust microfibers were continuously pulled from the oil-water interface. The resultant microfibers exhibited comparable mechanical and thermal properties but different aqueous stability. Combining PEG-bisTz2 and PEG-bisTz3 with a dangling arginine-glycine-aspartic acid (RGD) peptide in the aqueous phase yielded degradable fibers that supported the attachment and growth of primary vocal fold fibroblasts. The degradable and cell-adhesive hydrogel microfibers are expected to find utility in a wide array of tissue engineering applications.

The Development of ICT-Based Exercise Rehabilitation Service Contents for Patients with Musculoskeletal Disorders and Stroke.

Exercise rehabilitation services connecting hospitals and communities increase patient participation and improve quality of life by reducing medical expenses. South Korea's multi-ministerial governments have been working together to develop ICT-based hospital-community-linked services to create an exercise program that the public can easily use. This study aims to develop the exercise rehabilitation service components for the application and prescription of ICT-based exercise programs implemented in hospitals and communities. A literature review was conducted, and an expert committee was comprised to classify the components of exercise rehabilitation services. As a result, we classified the first components as functional classification, rehabilitation area, equipment uses, exercise type, frequency, and intensity. Subsequently, exercise programs were developed by applying the first components. Based on the purpose of exercise rehabilitation, we classified the representative standard exercise and grouped the same exercise movements using tools and exercise machines. The finding of this study will help to give the correct exercise prescription and manage patients' improvement process for exercise instructors. In addition, it guides patients in need of exercise rehabilitation to participate in an accurate and safe exercise in the community. This study is a novel attempt to develop ICT based hospital-community-linked exercise rehabilitation service for patients.

Development and Evaluation of a Classified and Tailored Community-Based Exercise Program According to the Mobility Level of People with Stroke Using the Knowledge to Action Framework.

Attempts to classify the mobility levels of people with stroke (PWS) for a tailored exercise program in community settings have been few. We developed and evaluated a classified and tailored community-based (CTC) exercise program according to the mobility level of PWS. Forty-two PWS were classified into the Supine and Sitting, Sitting and Standing, and Standing and Gait groups, based on a newly developed classification model and participated in a group-based CTC exercise program for 1 h/day twice/week for 10 weeks. The health outcome measures were blood pressure, lipid profile, glucose control, body composition, ventilatory capacity, and physical and psychological function. The rate of agreement on classification results among the physiotherapists was analysed. For all participants, significant improvements were noted in the blood pressure, lipid profile, body composition, ventilatory capacity, and physical and psychological function. The lower mobility groups showed significant improvements in a greater number of health outcomes than the higher mobility group. The physiotherapists' agreement regarding the classification results was 91.16 ± 5.14%, verifying the model's possible high relevance to the community. The effective improvement in participant health implied that the CTC exercise program was well tailored to the participants' mobility levels, particularly the lower mobility groups.

Characterization of Anti-Inflammatory and Antioxidant Constituents from Scutellaria baicalensis Using LC-MS Coupled with a Bioassay Method.

An effective and previously demonstrated screening method for active constituents in natural products using LC-MS coupled with a bioassay was reported in our earlier studies. With this, the current investigation attempted to identify bioactive constituents of Scutellaria baicalensis through LC-MS coupled with a bioassay. Peaks at broadly 17-20 and 24-25 min on the MS chromatogram displayed an inhibitory effect on NO production in lipopolysaccharide-induced BV2 microglia cells. Similarly, peaks at roughly 17-19 and 22 min showed antioxidant activity with an 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)/2,2-diphenyl-1- picrylhydrazyl (DPPH) assay. For confirmation of LC-MS coupled with a bioassay, nine compounds (1-9) were isolated from an MeOH extract of S. baicalensis. As we predicted, compounds 1, 8, and 9 significantly reduced lipopolysaccharide (LPS)-induced NO production in BV2 cells. Likewise, compounds 5, 6, and 8 exhibited free radical-scavenging activities with the ABTS/DPPH assay. In addition, the structural similarity of the main components was confirmed by analyzing the total extract and EtOAc fractions through molecular networking. Overall, the results suggest that the method comprised of LC-MS coupled with a bioassay can effectively predict active compounds without an isolation process, and the results of molecular networking predicted that other components around the active compound node may also be active.

Feasibility study on evaluating uranium enrichment with the High Resolution Gamma-Ray Spectrometry and X-ray fluorescence.

The uranium enrichment of the environmental sample should be analyzed to verify the declared information for the nuclear safeguards. The High-Resolution Gamma Spectrometry (HRGS) and Monochromatic Micro X-ray Fluorescence (MMXRF) is able to analyze the sample with a short detection time and high reproducibility. These are the advantage to measure the samples for screening before laboratory analysis. This study concentrated on uranium enrichment evaluation with the gamma-ray emission counts of 235U isotope (@185.7 keV) detected with the HRGS and counts of total uranium elements detected by MMXRF. As a result, the measured data were calculated for the uranium enrichment in three different ways: (i) Activity of 235U with the HRGS and mass of total uranium with the MMXRF, (ii) counts 235U with the HRGS and counts of total uranium, and (iii) activity of 235U and 238U with the HRGS. Based on the comparison with the mass spectrometry, method (iii) is able to derive the uranium enrichment the most accurately. However, method (ii) provides enough information for the screening to sort the sample for which laboratory analysis is necessary, when the sample's equilibrium status is not guaranteed.

Rapid Bioorthogonal Chemistry Enables in Situ Modulation of the Stem Cell Behavior in 3D without External Triggers.

Chemical modification of engineered microenvironments surrounding living cells represents a means for directing cellular behaviors through cell-matrix interactions. Presented here is a temporally controlled method for modulating the properties of biomimetic, synthetic extracellular matrices (ECM) during live cell culture employing the rapid, bioorthogonal tetrazine ligation with trans-cyclooctene (TCO) dienophiles. This approach is diffusion-controlled, cytocompatible, and does not rely on light, catalysts, or other external triggers. Human bone-marrow-derived mesenchymal stem cells (hMSCs) were initially entrapped in a hydrogel prepared using hyaluronic acid carrying sulfhydryl groups (HA-SH) and a hydrophilic polymer bearing both acrylate and tetrazine groups (POM-AT). Inclusion of a matrix metalloprotease (MMP)-degradable peptidic cross-linker enabled hMSC-mediated remodeling of the synthetic environment. The resultant network displayed dangling tetrazine groups for subsequent conjugation with TCO derivatives. Two days later, the stiffness of the matrix was increased by adding chemically modified HA carrying multiple copies of TCO (HA-TCO) to the hMSC growth media surrounding the cell-laden gel construct. In response, cells developed small processes radially around the cell body without a significant alteration of the overall shape. By contrast, modification of the 3D matrix with a TCO-tagged cell-adhesive motif caused the resident cells to undergo significant actin polymerization, changing from a rounded shape to spindle morphology with long cellular processes. After additional 7 days of culture in the growth media, quantitative analysis showed that, at the mRNA level, RGD tagging upregulated cellular expression of MMP1, but downregulated the expression of collagen I/III and tenascin C. RGD tagging, however, was not sufficient to induce the classic osteoblastic, chondrogenic, adipogenic, or fibroblastic/myofibroblastic differentiation. The modular approach allows facile manipulation of synthetic ECM to modulate cell behavior, thus potentially applicable to the engineering of functional tissues or tissue models.

Mediating effect of emotional/behavioral problems and academic competence between parental abuse/neglect and school adjustment.

The current study examined the mediating effects of emotional/behavioral problems and academic competence between parental abuse/neglect and a child's school adjustment by investigating 2070 student surveys from the Korean Child Youth Panel Study (KCYPS). A path analysis yielded the following key findings. Firstly, childhood abuse and neglect showed a significant negative and direct effect on school adjustment. It is particularly important to note that the effect of neglect was bigger than that of abuse in this study. Secondly, emotional/behavioral problems were found to partially mediate between abuse/neglect and school adjustment. Thirdly, academic competence partially mediated the effect of neglect on school adjustment, while it did not mediate the effect of abuse on school adjustment. The indirect effect of parental neglect via emotional/behavioral problems and academic competence was stronger than that of parental abuse. The influence of parental abuse and neglect on children's school adjustments was discussed in terms of emotional/behavioral problems and academic competence considering unique Korean cultural context.

A rare case of multiple pituitary adenomas in an adolescent Cushing disease presenting as a vertebral compression fracture.

Cushing disease in children and adolescents, especially with multiple pituitary adenomas (MPAs), is very rare. We report 17-year-old boy with MPAs. He presented with a vertebral compression fracture, weight gain, short stature, headache, and hypertension. On magnetic resonance imaging (MRI), only a left pituitary microadenoma was found. After surgery, transient clinical improvement was observed but headache and hypertension were observed again after 3 months later. Follow-up MRI showed a newly developed right pituitary microadenoma 6 months after the surgery. The need for careful clinical and radiographic follow-up should be emphasized in the search for potential MPAs in patients with persistent Cushing disease.

Multiplex Polymerase Chain Reaction for Identification of Shigellae and Four Shigella Species Using Novel Genetic Markers Screened by Comparative Genomics.

In the detection of Shigella species using molecular biological methods, previously known genetic markers for Shigella species were not sufficient to discriminate between Shigella species and diarrheagenic Escherichia coli. The purposes of this study were to screen for genetic markers of the Shigella genus and four Shigella species through comparative genomics and develop a multiplex polymerase chain reaction (PCR) for the detection of shigellae and Shigella species. A total of seven genomic DNA sequences from Shigella species were subjected to comparative genomics for the screening of genetic markers of shigellae and each Shigella species. The primer sets were designed from the screened genetic markers and evaluated using PCR with genomic DNAs from Shigella and other bacterial strains in Enterobacteriaceae. A novel Shigella quintuplex PCR, designed for the detection of Shigella genus, S. dysenteriae, S. boydii, S. flexneri, and S. sonnei, was developed from the evaluated primer sets, and its performance was demonstrated with specifically amplified results from each Shigella species. This Shigella multiplex PCR is the first to be reported with novel genetic markers developed through comparative genomics and may be a useful tool for the accurate detection of the Shigella genus and species from closely related bacteria in clinical microbiology and food safety.

Relationship of the Cold-Heat Sensation of the Limbs and Abdomen with Physiological Biomarkers.

The present study explored the relationship between the regional Cold-Heat sensation, the key indicator of the Cold-Heat patterns in traditional East Asian medicine (TEAM), and various biomarkers in Korean population. 734 apparently healthy volunteers aged 20 years and older were enrolled. Three scale self-report questions on the general thermal feel in hands, legs, and abdomen were examined. We found that 65% of women tended to perceive their body, particularly their hands and legs, to be cold, versus 25% of men. Energy expenditure and temperature load at resting state were lower in women, independently of body mass index (BMI). Those with warm hands and warm legs had a 0.74 and 0.52 kg/m2 higher BMI than those with cold hands and cold legs, respectively, regardless of age, gender, and body weight. Norepinephrine was higher, whereas the dynamic changes in glucose and insulin during an oral glucose tolerance test were lower in those with cold extremities, particularly hands. No consistent differences in biomarkers were found for the abdominal dimension. These results suggest that gender, BMI, the sympathetic nervous system, and glucose metabolism are potential determinants of the Cold-Heat sensation in the hands and legs, but not the abdomen.

High-performance strategy of a simulated moving bed chromatography by simultaneous control of product and feed streams under maximum allowable pressure drop.

In this study, a novel operating strategy was developed to improve the separation performance of simulated moving bed (SMB) chromatography by the simultaneous control of product outlet streams and feed inlet stream (SimCon). The SimCon operation can achieve a high separation performance without exceeding the maximum allowable pressure drop in an SMB system. The SimCon operation consisted of three steps within a single switching period: the initial, middle, and last steps. The extract port and feed-inlet port were closed at the initial step, but the raffinate port was closed at the last step. Therefore, in the SimCon strategy, we introduce two additional operating variables in a switching period, namely the middle time and middle length. In the SimCon operation, the middle step is a key factor to achieving a good separation performance because concentration profiles can be well controlled by two new middle-step variables. The SimCon operation showed outstanding results compared with those of the corresponding conventional SMB and other stream-control strategies in terms of purity, recovery, productivity, and eluent consumption. Because the SimCon operation can be operated with smaller flow and pressure fluctuations than other flow-rate-control strategies and improves the column efficiency, it is expected that the strategy can be practically adapted to real SMB processes with a good separation performance.