Artificial intelligence-based tools with automated segmentation and measurement on CT images to assist accurate and fast diagnosis in acute pancreatitis.

PURPOSE: To develop an artificial intelligence (AI) tool with automated pancreas segmentation and measurement of pancreatic morphological information on CT images to assist improved and faster diagnosis in acute pancreatitis. METHODS: This study retrospectively contained 1124 patients suspected for AP and received non-contrast and enhanced abdominal CT examination between September 2013 to September 2022. Patients were divided into training (N = 688), validation (N = 145), testing dataset (N = 291, N = 104 for normal pancreas, N = 98 for AP, N = 89 for AP complicated with PDAC (AP&PDAC)). A model based on convolutional neural network (MSAnet) was developed. The pancreas segmentation and measurement were performed via eight open-source models and MSAnet based tools, and the efficacy was evaluated using Dice similarity coefficient (DSC) and Intersection over union (IoU). The DSC and IoU for patients with different ages were also compared. The outline of tumor and edema in the AP and were segmented by clustering. The diagnostic efficacy for radiologists with or without the assistance of MSAnet tool in AP and AP&PDAC was evaluated using receiver operation curve and confusion matrix. RESULTS: Among all models, MSAnet based tool showed best performance on the training and validation dataset, and had high efficacy on testing dataset. The performance was age-affected. With assistance of the AI tool, the diagnosis time was significantly shortened by 26.8% and 32.7% for junior and senior radiologists, respectively. The area under curve in diagnosis of AP was improved from 0.91 to 0.96 for junior radiologist and 0.98 to 0.99 for senior radiologist. In AP&PDAC diagnosis, AUC was increased from 0.85 to 0.92 for junior and 0.97 to 0.99 for senior. CONCLUSION: MSAnet based tools showed good pancreas segmentation and measurement performance, which help radiologists improve diagnosis efficacy and workflow in both AP and AP with PDAC conditions. ADVANCES IN KNOWLEDGE: This study developed an AI tool with automated pancreas segmentation and measurement and provided evidence for AI tool assistance in improving the workflow and accuracy of AP diagnosis.

Predicting Osteoporosis and Osteopenia by Fusing Deep Transfer Learning Features and Classical Radiomics Features Based on Single-Source Dual-energy CT Imaging.

RATIONALE AND OBJECTIVES: To develop and validate a predictive model for osteoporosis and osteopenia prediction by fusing deep transfer learning (DTL) features and classical radiomics features based on single-source dual-energy computed tomography (CT) virtual monochromatic imaging. METHODS: A total of 606 lumbar vertebrae with dual-energy CT imaging and quantitative CT (QCT) evaluation were included in the retrospective study and randomly divided into the training (n = 424) and validation (n = 182) cohorts. Radiomics features and DTL features were extracted from 70-keV monochromatic CT images, followed by feature selection and model construction, radiomics and DTL features models were established. Then, we integrated the selected two types of features into a features fusion model. We developed a two-level classifier for the hierarchical pairwise classification of each vertebra. All the vertebrae were first classified into osteoporosis and non-osteoporosis groups, then non-osteoporosis group was classified into osteopenia and normal groups. QCT was used as reference. The predictive performance and clinical usefulness of three models were evaluated and compared. RESULTS: The area under the curve (AUC) of the features fusion, radiomics and DTL models for the classification between osteoporosis and non-osteoporosis were 0.981, 0.999, 0.997 in the training cohort and 0.979, 0.943, 0.848 in the validation cohort. Furthermore, the AUCs of the previously mentioned models for the differentiation between osteopenia and normal were 0.994, 0.971, 0.996 in the training cohort and 0.990, 0.968, 0.908 in the validation cohort. The overall accuracy of the previously mentioned models for two-level classifications was 0.979, 0.955, 0.908 in the training cohort and 0.918, 0.885, 0.841 in the validation cohort. Decision curve analysis showed that all models had high clinical value. CONCLUSION: The feature fusion model can be used for osteoporosis and osteopenia prediction with improved predictive ability over a radiomics model or a DTL model alone.

E3 ubiquitin ligase UBR5 modulates circadian rhythm by facilitating the ubiquitination and degradation of the key clock transcription factor BMAL1.

The circadian clock is the inner rhythm of life activities and is controlled by a self-sustained and endogenous molecular clock, which maintains a ~ 24 h internal oscillation. As the core element of the circadian clock, BMAL1 is susceptible to degradation through the ubiquitin-proteasome system (UPS). Nevertheless, scant information is available regarding the UPS enzymes that intricately modulate both the stability and transcriptional activity of BMAL1, affecting the cellular circadian rhythm. In this work, we identify and validate UBR5 as a new E3 ubiquitin ligase that interacts with BMAL1 by using affinity purification, mass spectrometry, and biochemical experiments. UBR5 overexpression induced BMAL1 ubiquitination, leading to diminished stability and reduced protein level of BMAL1, thereby attenuating its transcriptional activity. Consistent with this, UBR5 knockdown increases the BMAL1 protein. Domain mapping discloses that the C-terminus of BMAL1 interacts with the N-terminal domains of UBR5. Similarly, cell-line-based experiments discover that HYD, the UBR5 homolog in Drosophila, could interact with and downregulate CYCLE, the BMAL1 homolog in Drosophila. PER2-luciferase bioluminescence real-time reporting assay in a mammalian cell line and behavioral experiments in Drosophila reveal that UBR5 or hyd knockdown significantly reduces the period of the circadian clock. Therefore, our work discovers a new ubiquitin ligase UBR5 that regulates BMAL1 stability and circadian rhythm and elucidates the underlying molecular mechanism. This work provides an additional layer of complexity to the regulatory network of the circadian clock at the post-translational modification, offering potential insights into the modulation of the dysregulated circadian rhythm.

Increased water content in multifidus muscles of young adults with chronic nonspecific low back pain detected by dual-energy CT and MRI.

OBJECTIVES: To demonstrate the feasibility of better diagnosing young adults with chronic nonspecific low back pain (CNLBP) by measuring water content in paraspinal muscles using water-muscle decomposition technique in dual-energy CT (DECT) and T2-mapping in MRI. METHODS: This prospective cross-sectional study included 110 young individuals (56 with CNLBP at age of 25.7 ± 2.0 years and 54 of asymptomatic at age of 25.1 ± 1.9 years) who underwent both MRI and DECT on the spine. T2 values on T2 mapping in MRI and water density (WD) value on water(muscle) images in DECT were generated at the L1-L4 levels for erector spinae muscle and L2-L5 for multifidus muscle. Pain duration time, Oswestry Disability Index (ODI), Visual Analogue Scale (VAS) were recorded for CNLBP patients. Difference of T2 value and WD between the two patient groups, and correlations between T2 value and WD, and T2 value and WD with clinical indicators were analyzed. RESULTS: Compared with asymptomatic participants, the mean WD of multifidus muscle at L4-L5 and mean T2 values of multifidus muscle at L5 were significantly higher in CNLBP patients (all P < 0.05). T2 values had moderate to strong positive correlations (r = 0.34-0.60, all P < 0.05) with DECT WD in CNLBP patients and healthy volunteers. There was a weak correlation between VAS and WD in L5-level multifidus muscle (r = 0.29, P < 0.05). CONCLUSIONS: The T2 values in MRI and WD in DECT are higher in multifidus muscles of lower vertebra levels for young CNLBP patients, and there exists positive correlation between WD and T2 values, providing useful information for diagnosing CNLBP.

TFE3-Rearranged PEComa/PEComa-like Neoplasms: Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy.

Since their original description as a distinctive neoplastic entity, ~50 TFE3-rearranged perivascular epithelioid cell tumors (PEComas) have been reported. We herein report 25 new TFE3-rearranged PEComas and review the published literature to further investigate their clinicopathologic spectrum. Notably, 5 of the 25 cases were associated with a prior history of chemotherapy treatment for cancer. This is in keeping with prior reports, based mainly on small case series, with overall 11% of TFE3-rearranged PEComas being diagnosed postchemotherapy. The median age of our cohort was 38 years. Most neoplasms demonstrated characteristic features such as nested architecture, epithelioid cytology, HMB45 positive, and muscle marker negative immunophenotype. SFPQ was the most common TFE3 fusion partner present in half of the cases, followed by ASPSCR1 and NONO genes. Four of 7 cases in our cohort with meaningful follow-up presented with or developed systemic metastasis, while over half of the reported cases either recurred locally, metastasized, or caused patient death. Follow-up for the remaining cases was limited (median 18.5 months), suggesting that the prognosis may be worse. Size, mitotic activity, and necrosis were correlated with aggressive behavior. There is little evidence that treatment with MTOR inhibitors, which are beneficial against TSC-mutated PEComas, is effective against TFE3-rearranged PEComas: only one of 6 reported cases demonstrated disease stabilization. As co-expression of melanocytic and muscle markers, a hallmark of conventional TSC-mutated PEComa is uncommon in the spectrum of TFE3-rearranged PEComa, an alternative terminology may be more appropriate, such as "TFE3-rearranged PEComa-like neoplasms," highlighting their distinctive morphologic features and therapeutic implications.

Detecting bone marrow infiltration in nonosteolytic multiple myeloma through separation of hydroxyapatite via the two-material decomposition technique in spectral computed tomography.

Background: Conventional computed tomography (CT) has low sensitivity for the diagnosis of bone marrow infiltration in nonosteolytic multiple myeloma (NOL-MM). This study aimed to compare the performance of the two-material decomposition technique of spectral CT with the removal of X-ray absorption components of calcium (Ca) versus that of hydroxyapatite (HAP) for diagnosis of NOL-MM. Methods: From October 2022 to March 2023, a total of 41 consecutive patients with MM without focal bone lesions undergoing chest spectral CT and thoracic spine magnetic resonance imaging (MRI) in Fujian Medical University Union Hospital were prospectively enrolled; meanwhile, another set of 41 age- and sex-matched healthy consecutive participants were selected as a comparison group. Based on MRI findings, patients with MM were classified with a diffuse infiltration pattern MM (DP-MM) or a normal pattern MM (NP-MM). Regions of interest (ROIs) were manually drawn on vertebrae. CT values of 70-keV images and basic material density within the ROIs were stored. The basic two-material pairs included a Ca-related pair (Ca-X) and an HAP-related pair (HAP-X), with X referring to fat, water, or muscle. Material density values DCa(X), DX(Ca), DHAP(X), and DX(HAP) were each used to diagnose MM, and the area under the receiver operating characteristic curve (AUC) was used to assess diagnostic performance. Results: The 41 patients with NOL-MM included 30 with DP-MM and 11 with NP-MM. CT value, DCa(X), and DHAP(X) were comparable between the NOL-MM, DP-MM, NP-MM, and comparison groups. DX(HAP) was better than DX(Ca) for distinguishing the NOL-MM group from the comparison group {AUC [95% confidence interval (CI)], 0.874 (0.800, 0.949) vs. 0.737 (0.630, 0.844); P=0.02}, the DP-MM group from the comparison group [AUC (95% CI), 0.933 (0.878, 0.989) vs. 0.785 (0.677, 0.894); P=0.01], the NP-MM group from the comparison group [AUC (95% CI), 0.714 (0.540, 0.888) vs. 0.605 (0.429, 0.782); P=0.03], and the DP-MM group from the NP-MM group [AUC (95% CI), 0.809 (0.654, 0.964) vs. 0.736 (0.566, 0.907); P=0.049]. The diagnostic performance of DX(HAP) and DX(Ca) was influenced only by the removed material, while the X material had no influence. Conclusions: The spectral CT two-material decomposition technique with removal of X-ray absorption components of HAP is useful for diagnosis of NOL-MM, irrespective of the paired material.

Recent advances in microbial fuel cell-based self-powered biosensors: a comprehensive exploration of sensing strategies in both anode and cathode modes.

With the rapid development of society, it is of paramount importance to expeditiously assess environmental pollution and provide early warning of toxicity risks. Microbial fuel cell-based self-powered biosensors (MFC-SPBs) have emerged as a pivotal technology, obviating the necessity for external power sources and aligning with the prevailing trends toward miniaturization and simplification in biosensor development. In this case, vigorous advancements in MFC-SPBs have been acquired in past years, irrespective of whether the target identification event transpires at the anode or cathode. The present article undertakes a comprehensive review of developed MFC-SPBs, categorizing them into substrate effect and microbial activity effect based on the nature of the target identification event. Furthermore, various enhancement strategies to improve the analytical performance like accuracy and sensitivity are also outlined, along with a discussion of future research trends and application prospects of MFC-SPBs for their better developments.

Ring Chromosomes in Hematological Malignancies Are Associated with TP53 Gene Mutations and Characteristic Copy Number Variants.

Ring chromosomes (RC) are present in <10% of patients with hematological malignancies and are associated with poor prognosis. Until now, only small cohorts of patients with hematological neoplasms and concomitant RCs have been cytogenetically characterized. Here, we performed a conventional chromosome analysis on metaphase spreads from >13,000 patients diagnosed with hematological malignancies at the Johns Hopkins University Hospital and identified 98 patients with RCs-90 with myeloid malignancies and 8 with lymphoid malignancies. We also performed a targeted Next-Generation Sequencing (NGS) assay, using a panel of 642 cancer genes, to identify whether these patients harbor relevant pathogenic variants. Cytogenetic analyses revealed that RCs and marker chromosomes of unknown origin are concurrently present in most patients by karyotyping, and 93% of patients with NGS data have complex karyotypes. A total of 72% of these individuals have pathogenic mutations in TP53, most of whom also possess cytogenetic abnormalities resulting in the loss of 17p, including the loss of TP53. All patients with a detected RC and without complex karyotypes also lack TP53 mutations but have pathogenic mutations in TET2. Further, 70% of RCs that map to a known chromosome are detected in individuals without TP53 mutations. Our data suggest that RCs in hematological malignancies may arise through different mechanisms, but ultimately promote widespread chromosomal instability.

Effect of Rosiglitazone, the Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, on Apoptosis, Inflammatory Cytokines and Oxidative Stress in pentylenetetrazole-Induced Seizures in Kindled Mice.

A growing body of evidence has shown that seizure can trigger inflammatory cascades through increasing the expression of several inflammatory cytokines. It has been proved that peroxisome proliferator-activated receptor-γ agonists have immunomodulatory, anti-inflammatory, and neuroprotective effects beyond the putative hypoglycemic effects. Thus, we investigated the inhibitory effect of rosiglitazone on the development of pentylenetetrazol (PTZ)-induced kindling via affecting the inflammatory pathway. Male C57BL/6 mice were randomly divided into vehicle group (0.1% DMSO), PTZ-group and rosiglitazone-PTZ-group. Kindling was induced by the administration of PTZ (40 mg/kg, i.p) every other day and mice were observed for 20 min after each PTZ injection. Twenty-four hours after the last dose, animals were euthanized and hippocampus was isolated. The level of Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Catalase (CAT) activity were quantified in hippocampus by biochemical methods. The protein levels of IL-1ß, IL-6, IL-10, IFN-γ, TNF-α, caspase-3, iNOS, PPAR-γ, Bcl-2, or Bax factors were measured with western blotting. Also, the quantitative real-time PCR were used to evaluate the mRNA expression of those factors. Pretreatment with rosiglitazone significantly prevented the progression of kindling in comparison with control group. The rosiglitazone significantly decreased the MDA level and increased the CAT, and SOD levels in the rosiglitazone treated mice compared to those in the PTZ group (P < 0.01). Using real-time PCR and Western blotting assay, similar results were obtained. The expression levels of IL-1ß, IL-6, IL-10, IFN-γ, TNF-α, Bax or PPAR-γ were significantly changed in the brain. The results of this study suggest that effect of rosiglitazone may be crucial in its ability to protect against the neuronal damage caused by PTZ induced seizure.

Hyaluronan-based hydrogel integrating exosomes for traumatic brain injury repair by promoting angiogenesis and neurogenesis.

With wide clinical demands, therapies for traumatic brain injury (TBI) are far from satisfactory. Combining the merits of stem cells but avoiding the risk of immunologic rejection, bone marrow mesenchymal stem cell-derived exosomes (BME) attract increasing interests and have been proved effective for TBI repair by intravenous or in situ injection. However, difficulties in sustained delivery or aggregation in lesion sites remain obstacle to using BME for TBI. Inspired by that hydrogels are promising to bridge the destroyed neural gap and provide neural niches, we raised a novel strategy of incorporating BME into hyaluronan-collagen hydrogel (DHC-BME) to achieve both mimicking of brain matrix and steady release of exosomes, and thus realizing TBI repair. External characterizations proved that the BME and DHC synergistically promoted neural stem cells (NSCs) differentiation into neurons and oligodendrocytes while inhibited astrocytes differentiation. DHC-BME induced angiogenesis and neurogenesis, from endogenous NSC recruitment to neuronal differentiation and vascularization to synergistically promote axonal regeneration, remyelination, synapse formation and even brain structural remodeling, and lastly, neurological functional recovery of TBI.

Prediction of osteoporosis using radiomics analysis derived from single source dual energy CT.

BACKGROUND: With the aging population of society, the incidence rate of osteoporosis is increasing year by year. Early diagnosis of osteoporosis plays a significant role in the progress of disease prevention. As newly developed technology, computed tomography (CT) radiomics could discover radiomic features difficult to recognize visually, providing convenient, comprehensive and accurate osteoporosis diagnosis. This study aimed to develop and validate a clinical-radiomics model based on the monochromatic imaging of single source dual-energy CT for osteoporosis prediction. METHODS: One hundred sixty-four participants who underwent both single source dual-energy CT and quantitative computed tomography (QCT) lumbar-spine examination were enrolled in a study cohort including training datasets (n = 114 [30 osteoporosis and 84 non-osteoporosis]) and validation datasets (n = 50 [12 osteoporosis and 38 non-osteoporosis]). One hundred seven radiomics features were extracted from 70-keV monochromatic CT images. With QCT as the reference standard, a radiomics signature was built by using least absolute shrinkage and selection operator (LASSO) regression on the basis of reproducible features. A clinical-radiomics model was constructed by incorporating the radiomics signature and a significant clinical predictor (age) using multivariate logistic regression analysis. Model performance was assessed by its calibration, discrimination and clinical usefulness. RESULTS: The radiomics signature comprised 14 selected features and showed good calibration and discrimination in both training and validation cohorts. The clinical-radiomics model, which incorporated the radiomics signature and a significant clinical predictor (age), also showed good discrimination, with an area under the receiver operating characteristic curve (AUC) of 0.938 (95% confidence interval, 0.903-0.952) in the training cohort and an AUC of 0.988 (95% confidence interval, 0.967-0.998) in the validation cohort, and good calibration. The clinical-radiomics model stratified participants into groups with osteoporosis and non-osteoporosis with an accuracy of 94.0% in the validation cohort. Decision curve analysis (DCA) demonstrated that the radiomics signature and the clinical-radiomics model were clinically useful. CONCLUSIONS: The clinical-radiomics model incorporating the radiomics signature and a clinical parameter had a good ability to predict osteoporosis based on dual-energy CT monoenergetic imaging.

Associations between paraspinal muscles fatty infiltration and lumbar vertebral bone mineral density - An investigation by fast kVp switching dual-energy CT and QCT.

Purpose: To investigate the relationship between paraspinal muscles fat content and lumbar bone mineral density (BMD). Methods: A total of 119 participants were enrolled in our study (60 males, age: 50.88 ± 17.79 years, BMI: 22.80 ± 3.80 kg·m-2; 59 females, age: 49.41 ± 17.69 years, BMI: 22.22 ± 3.12 kg·m-2). Fat content of paraspinal muscles (erector spinae (ES), multifidus (MS), and psoas (PS)) were measured at (ES L1/2-L4/5; MS L2/3-L5/S1; PS L2/3-L5/S1) levels using dual-energy computed tomography (DECT). Quantitative computed tomography (QCT) was used to assess BMD of L1 and L2. Linear regression analysis was used to assess the relationship between BMD of the lumbar spine and paraspinal muscles fat content with age, sex, and BMI. The variance inflation factor (VIF) was used to detect the degree of multicollinearity among the variables. P < .05 was considered to indicate a statistically significant difference. Results: The paraspinal muscles fat content had a fairly significant inverse association with lumbar BMD after controlling for age, sex, and BMI (adjusted R 2 = 0.584-0.630, all P < .05). Conclusion: Paraspinal muscles fat content was negatively associated with BMD.Paraspinal muscles fatty infiltration may be considered as a potential marker to identify BMD loss.

Neuroinduction and neuroprotection co-enhanced spinal cord injury repair based on IL-4@ZIF-8-loaded hyaluronan-collagen hydrogels with nano-aligned and viscoelastic cues.

Spontaneous recovery after spinal cord injury (SCI) is extremely limited since the severe inflammatory responses lead to secondary damage, and the diseased extracellular matrix (ECM) fails to provide inductive cues for nerve regeneration. To address these dilemmas, herein, we propose a biomaterial-based strategy combining neuroprotection and neuroinduction for SCI repair. Taking advantage of a microfluidic chip, we constructed imine-crosslinked aldehyde-methacrylate-hyaluronan/collagen hybrid hydrogel microfibers incorporating interleukin 4 (IL-4)-loaded ZIF-8 nanoparticles (IL4@ZIF-8 NPs). The hybrid hydrogel microfibers possess pivotal traits mimicking the natural ECM and hold neuroinductive nanoalignment and viscoelasticity, as well as the acidic microenvironment-responsive release of neuroprotective IL-4. Then, we elucidated the role of the tailored hydrogel microfibers in promoting the structural and functional recovery of SCI rats. The implanted hydrogel microfibers incorporating IL4@ZIF-8 NPs protected endogenous neural cells by promoting M2 polarization of recruited macrophages and suppressing inflammation. Additionally, the hydrogel microfibers enhanced neuronal differentiation, accelerated axonal regrowth, synapse formation and remyelination, resulting from their ECM-mimicking oriented nano-topography and viscoelasticity. Moreover, the locomotor function was also improved by the implanted microfibers combining neuroprotective cues and neuroinductive cues. This work not only paves the steps for the development of a novel class of multifunctional hydrogels that manipulate tissue behavior by modifying the cellular microenvironment but also provides intriguing insights for the repair of SCI and even other central nervous system (CNS) injuries via tissue engineering approaches.

A Bioactive and Photoresponsive Platform for Wireless Electrical Stimulation to Promote Neurogenesis.

Delivering electrical signals to neural cells and tissue has attracted increasing attention in the treatment of nerve injuries. Unlike traditional wired electrical stimulation, wireless and remote light stimulation provides less invasive and longer-lasting interfaces, holding great promise in the treatment of nerve injuries and neurodegenerative diseases, as well as human-computer interaction. Additionally, a bioactive matrix that bridges the injured gap and induces nerve regeneration is essential for injured nerve repair. However, it is still challenging to construct a 3D biomimetic cell niche with optoelectrical responsiveness. Herein, a bioactive platform for remote and wireless optoelectrical stimulation is established by incorporating hydrophilic poly(3-hexylthiophene) nanoparticles (P3HT NPs) into a biomimetic hydrogel matrix. Moreover, the hydrogel matrix is modified by varying the composition and/or the crosslinking degree to meet the needs of different application scenarios. When exposed to pulsed green light, P3HT NPs in hydrogels convert light signals into electrical signals, resulting in the generation of tens of picoampere photocurrent, which is proved to promote the growth of cortical neurons that covered by hydrogels and the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) encapsulated in hydrogels. This work is of great significance for the design of next-generation neural electrodes and scaffolds.

Semiconvertible Hyaluronic Hydrogel Enabled Red-Light-Responsive Reversible Mechanics, Adhesion, and Self-Healing.

Photoresponsive supramolecular hydrogels based on the host-guest interaction between cyclodextrin (CD) and azobenzene (Azo) are highly favored in "on-demand" biological applications. Nevertheless, most Azo/CD-based hydrogels are UV-responsive, exhibiting poor tissue penetrability and potential cytotoxicity; more importantly, the complete gel-sol transition under irradiation makes intelligent systems unstable. Here, we report a red-light-responsive semiconvertible hydrogel based on tetra-ortho-methoxy-substituted Azo (mAzo)- and CD-functionalized hyaluronic acid (HA). By integrating red-shifted-photoisomerized mAzo with HA, a biocompatible 625 nm-light-responsive polymeric guest with strengthened hydrogen bonding and weakened photoisomerization was synthesized. Upon alternating irradiation, mAzo-HA/CD-HA hydrogels obtained here exhibited reversible mechanical and structural dynamics, while avoiding complete gel-sol transition. This improved semiconvertibility remedies the lack of macroscopic resilience for dynamic system so as to endow supramolecular hydrogels with spatial-temporal mechanics, self-healing, and adhesion. Together with excellent cytocompatibility and manufacturability, these hydrogels show potential advantages in tissue engineering, especially for the regeneration of functional multi-tissue complex.

Aldehyde-methacrylate-hyaluronan profited hydrogel system integrating aligned and viscoelastic cues for neurogenesis.

Either oriented architecture or viscoelasticity is pivotal to neurogenesis, thus, native neural extracellular matrix derived-hyaluronan hydrogels with nano-orientation and viscoelasticity recapitulated might be instructive for neurogenesis, however it is still unexploited. Herein, based on aldehyde-methacrylate difunctionalized hyaluronan, by integrating imine kinetic modulation and microfluidic biofabrication, we construct a hydrogel system with orthogonal viscoelasticity and nano-topography. We then find the positive synergy effects of matrix nano-orientation and viscoelasticity not only on neurites outgrowth and elongation of neural cells, but also on neuronal differentiation of stem cells. Moreover, by implanting viscoelastic and nano-aligned hydrogels into lesion sites, we demonstrate the enhanced repair of spinal cord injury, including ameliorated pathological microenvironment, facilitated endogenous neurogenesis and functional axons regeneration as well as motor function restoration. This work supplies universal platform for preparing neuronal inducing hyaluronan-based hydrogels which might serve as promising therapeutic strategies for nerve injury.

Validation of Long Mononucleotide Repeat Markers for Detection of Microsatellite Instability.

Mismatch repair deficiency (dMMR) predicts response to immune checkpoint inhibitor therapy in solid tumors. Long mononucleotide repeat (LMR) markers may improve the interpretation of microsatellite instability (MSI) assays. Our cohorts included mismatch repair (MMR) proficient and dMMR colorectal cancer (CRC) samples, MMR proficient and dMMR endometrial cancer (EC) samples, dMMR prostate cancer samples, MSI-high (MSI-H) samples of other cancer types, and MSI-low (MSI-L) samples of various cancer types. MMR status was determined by immunohistochemical staining and/or MSI Analysis System Version 1.2 (V1.2). The sensitivity and specificity of the LMR MSI panel for dMMR detection were both 100% in CRC. The sensitivity values of the MSI V1.2 and LMR MSI panels in EC were 88% and 98%, respectively, and the specificity values were both 100%. The sensitivity of the LMR panel was 75% in dMMR prostate cancer detected by immunohistochemistry. The 22 samples of other cancer types that were previously classified as MSI-H were also classified as MSI-H using the LMR MSI panel. For the 12 samples that were previously classified as MSI-L, 1 sample was classified as microsatellite stable using the LMR MSI panel, 8 as MSI-L, and 3 as MSI-H. The LMR MSI panel showed high concordance to the MSI V1.2 panel in CRC and greater sensitivity in EC. The LMR MSI panel improves dMMR detection in noncolorectal cancers.

Antioxidative and Conductive Nanoparticles-Embedded Cell Niche for Neural Differentiation and Spinal Cord Injury Repair.

Following spinal cord injury (SCI), the transmission of electrical signals is interrupted, and an oxidative microenvironment is generated, hindering nerve regeneration and functional recovery. The strategies of regulating oxidative pathological microenvironment while restoring endogenous electrical signal transmission hold promise for SCI treatment. However, challenges are still faced in simply fabricating bioactive scaffolds with both antioxidation and conductivity. Herein, aiming to construct an antioxidative and conductive microenvironment for nerve regeneration, the difunctional polypyrrole (PPy) nanoparticles were developed and incorporated into bioactive collagen/hyaluronan hydrogel. Owing to the embedded PPy in hydrogel, the encapsulated bone marrow mesenchymal stem cells (BMSCs) can be protected from oxidative damage, and their neuronal differentiation was promoted by the synergy between conductivity and electrical stimulation, which is proved to be related to PI3K/Akt and the mitogen-activated protein kinase (MAPK) pathway. In SCI rats, the BMSC-laden difunctional hydrogel restored the transmission of bioelectric signals and inhibited secondary damage, thereby facilitating neurogenesis, resulting in prominent nerve regeneration and functional recovery. Overall, taking advantage of a difunctional nanomaterial to meet two essential requirements in SCI repair, this work provides intriguing insights into the design of biomaterials for nerve regeneration and tissue engineering.

Chinese Medicine Formula Huashibaidu Granule Early Treatment for Mild COVID-19 Patients: An Unblinded, Cluster-Randomized Clinical Trial.

Background: Previous research suggested that Chinese Medicine (CM) Formula Huashibaidu granule might shorten the disease course in coronavirus disease 2019 (COVID-19) patients. This research aimed to investigate the early treatment effect of Huashibaidu granule in well-managed patients with mild COVID-19. Methods: An unblinded cluster-randomized clinical trial was conducted at the Dongxihu FangCang hospital. Two cabins were randomly allocated to a CM or control group, with 204 mild COVID-19 participants in each cabin. All participants received conventional treatment over a 7 day period, while the ones in CM group were additionally given Huashibaidu granule 10 g twice daily. Participants were followed up to their clinical endpoint. The primary outcome was worsening symptoms before the clinical endpoint. The secondary outcomes were cure and discharge before the clinical endpoint and alleviation of composite symptoms after the 7 days of treatment. Results: All 408 participants were followed up to their clinical endpoint and included in statistical analysis. Baseline characteristics were comparable between the two groups (P > 0.05). The number of worsening patients in the CM group was 5 (2.5%), and that in the control group was 16 (7.8%) with a significant difference between groups (P = 0.014). Eight foreseeable mild adverse events occurred without statistical difference between groups (P = 0.151). Conclusion: Seven days of early treatment with Huashibaidu granule reduced the likelihood of worsening symptoms in patients with mild COVID-19. Our study supports Huashibaidu granule as an active option for early treatment of mild COVID-19 in similar well-managed medical environments. Clinical Trial Registration:www.chictr.org.cn/showproj.aspx?proj=49408, identifier: ChiCTR2000029763.

Combination of Hua Shi Bai Du granule (Q-14) and standard care in the treatment of patients with coronavirus disease 2019 (COVID-19): A single-center, open-label, randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of Hua Shi Bai Du Granule (Q-14) plus standard care compared with standard care alone in adults with coronavirus disease (COVID-19). STUDY DESIGN: A single-center, open-label, randomized controlled trial. SETTING: Wuhan Jinyintan Hospital, Wuhan, China, February 27 to March 27, 2020. PARTICIPANTS: A total of 204 patients with laboratory-confirmed COVID-19 were randomized into the treatment group and control group, consisting of 102 patients in each group. INTERVENTIONS: In the treatment group, Q-14 was administered at 10 g (granules) twice daily for 14 days, plus standard care. In the control group, patients were provided standard care alone for 14 days. MAIN OUTCOME MEASURE: The primary outcome was the conversion time for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral assay. Adverse events were analyzed in the safety population. RESULTS: Among the 204 patients, 195 were analyzed according to the intention-to-treat principle. A total of 149 patients (71 vs. 78 in the treatment and control groups, respectively) tested negative via the SARS-CoV-2 viral assay. There was no statistical significance in the conversion time between the treatment group and control group (Full analysis set: Median [interquartile range]: 10.00 [9.00-11.00] vs. 10.00 [9.00-11.00]; Mean rank: 67.92 vs. 81.44; P = 0.051). The recovery time for fever was shorter in the treatment group than in the control group. The disappearance rate of symptoms like cough, fatigue, and chest discomfort was significantly higher in the treatment group. In chest computed tomography (CT) examinations, the overall evaluation of chest CT examination after treatment compared with baseline showed that more patients improved in the treatment group. There were no significant differences in the other outcomes. CONCLUSION: The combination of Q-14 and standard care for COVID-19 was useful for the improvement of symptoms (such as fever, cough, fatigue, and chest discomfort), but did not result in a significantly higher probability of negative conversion in the SARS-CoV-2 viral assay. No serious adverse events were observed. TRIAL REGISTRATION: ChiCTR2000030288.