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Abstract Meniscal injury represents a common type of knee injury, accounting for over 50% of all knee injuries. The clinical diagnosis and treatment of meniscal injury heavily rely on magnetic resonance imaging (MRI). However, accurately diagnosing the meniscus from a comprehensive knee MRI is challenging due to its limited and weak signal, significantly impeding the precise grading of meniscal injuries. In this study, a visual interpretable fine grading (VIFG) diagnosis model has been developed to facilitate intelligent and quantified grading of meniscal injuries. Leveraging a multilevel transfer learning framework, it extracts comprehensive features and incorporates an attributional attention module to precisely locate the injured positions. Moreover, the attention-enhancing feedback module effectively concentrates on and distinguishes regions with similar grades of injury. The proposed method underwent validation on FastMRI_Knee and Xijing_Knee dataset, achieving mean grading accuracies of 0.8631 and 0.8502, surpassing the state-of-the-art grading methods notably in error-prone Grade 1 and Grade 2 cases. Additionally, the visually interpretable heatmaps generated by VIFG provide accurate depictions of actual or potential meniscus injury areas beyond human visual capability. Building upon this, a novel fine grading criterion was introduced for subtypes of meniscal injury, further classifying Grade 2 into 2a, 2b, and 2c, aligning with the anatomical knowledge of meniscal blood supply. It can provide enhanced injury-specific details, facilitating the development of more precise surgical strategies. The efficacy of this subtype classification was evidenced in 20 arthroscopic cases, underscoring the potential enhancement brought by intelligent-assisted diagnosis and treatment for meniscal injuries.

Objective: We aimed to develop an algorithm that accurately identifies children with Down syndrome (DS) using administrative data. Methods: We identified a cohort of children born between 2000 and 2017, enrolled in the Tennessee Medicaid Program (TennCare), who either had DS coded on their birth certificate or had a diagnosis listed using an International Classification of Diseases (ICD) code (suspected DS), and who received care at Vanderbilt University Medical Center, a comprehensive academic medical center, in the United States. Children with suspected DS were defined as having DS if they had (a) karyotype-confirmed DS indicated on their birth certificate; (b) karyotype-pending DS indicated on their birth certificate (or just DS if test type was not specified) and at least two healthcare encounters for DS during the first 6 years of life; or (c) at least three healthcare encounters for DS, with the first and last encounter separated by at least 30 days, during the first six years of life. The positive predictive value (PPV) of the algorithm and 95% confidence interval (CI) were reported. Results: Of the 411 children with suspected DS, 354 (86.1%) were defined as having DS by the algorithm. According to medical chart review, the algorithm correctly identified 347 children with DS (PPV = 98%, 95%CI: 96.0–99.0%). Of the 57 children the algorithm defined as not having DS, 50 (97.7%, 95%CI: 76.8–93.9%) were confirmed as not having DS by medical chart review. Conclusions: An algorithm that accurately identifies individuals with DS using birth certificate data and/or ICD codes provides a valuable tool to study DS using administrative data.

Increasing evidence indicates that mitochondrial fission imbalance plays an important role in delayed neuronal cell death. Our previous study found that photobiomodulation improved the motor function of rats with spinal cord injury. However, the precise mechanism remains unclear. To investigate the effect of photobiomodulation on mitochondrial fission imbalance after spinal cord injury, in this study, we treated rat models of spinal cord injury with 60-minute photobiomodulation (810 nm, 150 mW) every day for 14 consecutive days. Transmission electron microscopy results confirmed the swollen and fragmented alterations of mitochondrial morphology in neurons in acute (1 day) and subacute (7 and 14 days) phases. Photobiomodulation alleviated mitochondrial fission imbalance in spinal cord tissue in the subacute phase, reduced neuronal cell death, and improved rat posterior limb motor function in a time-dependent manner. These findings suggest that photobiomodulation targets neuronal mitochondria, alleviates mitochondrial fission imbalance-induced neuronal apoptosis, and thereby promotes the motor function recovery of rats with spinal cord injury.

Abstract Background Secondary spinal cord injury (SCI) often causes the aggravation of inflammatory reaction and nerve injury, which affects the recovery of motor function. Bone-marrow-derived macrophages (BMDMs) were recruited to the injured area after SCI, and the M1 polarization is the key process for inducing inflammatory response and neuronal apoptosis. We previously showed that photobiomodulation (PBM) can inhibit the polarization of M1 phenotype of BMDMs and reduce inflammation, but the underlying mechanisms are unclear. The purpose of this study is to explore the potential target and mechanism of PBM in treating SCI. Methods Transcriptome sequencing and bioinformatics analysis showed that long noncoding RNA taurine upregulated gene 1 (lncRNA TUG1) was a potential target of PBM. The expression and specific mechanism of lncRNA TUG1 were detected by qPCR, immunofluorescence, flow cytometry, western blotting, fluorescence in situ hybridization, and luciferase assay. The Basso mouse scale (BMS) and gait analysis were used to evaluate the recovery of motor function in mice. Results Results showed that lncRNA TUG1 may be a potential target of PBM, regulating the polarization of BMDMs, inflammatory response, and the axial growth of DRG. Mechanistically, TUG1 competed with TLR3 for binding to miR-1192 and attenuated the inhibitory effect of miR-1192 on TLR3. This effect protected TLR3 from degradation, enabling the high expression of TLR3, which promoted the activation of downstream NF-κB signal and the release of inflammatory cytokines. In vivo, PBM treatment could reduce the expression of TUG1, TLR3, and inflammatory cytokines and promoted nerve survival and motor function recovery in SCI mice. Conclusions Our study clarified that the lncRNA TUG1/miR-1192/TLR3 axis is an important pathway for PBM to inhibit M1 macrophage polarization and inflammation, which provides theoretical support for its clinical application in patients with SCI.

Abstract Mitochondrial transplantation is a promising treatment for spinal cord injury (SCI), but it has the disadvantage of low efficiency of mitochondrial transfer to targeted cells. Here, we demonstrated that Photobiomodulation (PBM) could promote the transfer process, thus augmenting the therapeutic effect of mitochondrial transplantation. In vivo experiments, motor function recovery, tissue repair, and neuronal apoptosis were evaluated in different treatment groups. Under the premise of mitochondrial transplantation, the expression of Connex36 (Cx36), the trend of mitochondria transferred to neurons, and its downstream effects, such as ATP production and antioxidant capacity, were evaluated after PBM intervention. In in vitro experiments, dorsal root ganglia (DRG) were cotreated with PBM and 18β‐GA (a Cx36 inhibitor). In vivo experiments showed that PBM combined with mitochondrial transplantation could increase ATP production and reduce oxidative stress and neuronal apoptosis levels, thereby promoting tissue repair and motor function recovery. In vitro experiments further verified that Cx36 mediated the transfer of mitochondria into neurons. PBM could facilitate this progress via Cx36 both in vivo and in vitro. The present study reports a potential method of using PBM to facilitate the transfer of mitochondria to neurons for the treatment of SCI.

Abstract Background African Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress. Objective To test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs. Methods Proof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 h. Outcomes were assessed at baseline, 2 and 4 h during the infusion. Main outcome measures Changes in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-h post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha). Results A total of 32 obese AA women were screened and fourteen completed the study (age 37.8 ± 10.70 years old, BMI 38.7 ± 3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007 ± 0.008 vs. − 0.002 ± 0.006 ng/sample, P = 0.016), and plasma (0.01 ± 0.02 vs. − 0.003 ± 0.01 ng/mL, P = 0.023). Galantamine also decreased IL-6 (11.4 ± 18.45 vs. 7.7 ± 15.10 pg/mL, P = 0.021) and TNFα levels (18.6 ± 16.33 vs. 12.9 ± 6.16 pg/mL, P = 0.021, 4-h post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5 ± 10.49 vs. 43.6 ± 13.38 during placebo pg/uL, P = 0.025). Conclusions In this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs. Trial registration: ClinicalTrials.gov identifiers NCT02365285.

Abstract Background Neurotoxic microglia and astrocytes begin to activate and participate in pathological processes after spinal cord injury (SCI), subsequently causing severe secondary damage and affecting tissue repair. We have previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM ameliorates neuroinflammation by modulating the activation of microglia and astrocytes after SCI. Methods Male Sprague–Dawley rats were randomly divided into three groups: a sham control group, an SCI + vehicle group and an SCI + PBM group. PBM was performed for two consecutive weeks after clip-compression SCI models were established. The activation of neurotoxic microglia and astrocytes, the level of tissue apoptosis, the number of motor neurons and the recovery of motor function were evaluated at different days post-injury (1, 3, 7, 14, and 28 days post-injury, dpi). Lipocalin 2 (Lcn2) and Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) signaling were regarded as potential targets by which PBM affected neurotoxic microglia and astrocytes. In in vitro experiments, primary microglia and astrocytes were irradiated with PBM and cotreated with cucurbitacin I (a JAK2-STAT3 pathway inhibitor), an adenovirus (shRNA-Lcn2) and recombinant Lcn2 protein. Results PBM promoted the recovery of motor function, inhibited the activation of neurotoxic microglia and astrocytes, alleviated neuroinflammation and tissue apoptosis, and increased the number of neurons retained after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also showed that Lcn2 and JAK2-STAT3 were mutually promoted and that PBM interfered with this interaction, inhibiting the activation of microglia and astrocytes. Conclusion Lcn2/JAK2-STAT3 crosstalk is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be suppressed by PBM.

It has been proved that endomorphin-2 (EM2) produced obvious analgesic effects in the spinal dorsal horn (SDH), which existed in our human bodies with remarkable affinity and selectivity for the μ-opioid receptor (MOR). Our previous study has demonstrated that EM2 made synapses with the spinoparabrachial projection neurons (PNs) in the SDH and inhibited their activities by reducing presynaptic glutamate release. However, the morphological features of EM2 and the spinoparabrachial PNs in the SDH have not been completely investigated. Here, we examined the morphological features of EM2 and the spinoparabrachial PNs by using triple fluorescence and electron microscopic immunohistochemistry. EM2-immunoreactive (-ir) afferents directly contacted with the spinoparabrachial PNs in lamina I of the SDH. Immunoelectron microscopy (IEM) were used to confirm that these contacts were synaptic connections. It was also observed that EM2-ir axon terminals contacting with spinoparabrachial PNs in lamina I contained MOR, substance P (SP) and vesicular glutamate transporter 2 (VGLUT2). In lamina II, MOR-ir neurons were observed to receive direct contacts from EM2-ir varicosities. The synaptic connections among EM2, MOR, SP, VGLUT2, and the spinoparabrachial PNs were also confirmed by IEM. In sum, our results supply morphological evidences for the analgesic effects of EM2 on the spinoparabrachial PNs in the SDH.

OBJECTIVES/GOALS: Children with Down syndrome are at increased risk of respiratory diseases including asthma. Prenatal antibiotic exposure has been shown to be associated with the development of childhood asthma. We aim to estimate the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome. METHODS/STUDY POPULATION: We conducted a retrospective cohort study of mother-child dyads of children with Down syndrome who were born 1995-2013. Both children and mothers were continuously enrolled in the Tennessee Medicaid Program (TennCare). Prenatal antibiotic exposure was measured using mother’s prescription fill records. Childhood asthma was defined between age 4.5-6 years by asthma-related healthcare encounters and asthma-specific medication fills. We assessed the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome using modified Poisson regression adjusting for maternal age, race, residence, education, marital status, smoking during pregnancy, maternal asthma status, delivery method, number of siblings, and children’s sex. RESULTS/ANTICIPATED RESULTS: Among 346 mother-child dyads of children with Down syndrome, 273 (78.9%) children were exposed prenatally to antibiotics and 104 (30.0%) had asthma by age 4.5-6 years. Among those who were exposed to at least one course, the median antibiotic course equaled 2 (interquartile range: 1-4). Prenatal antibiotic exposure was associated with a 20% increase in risk of childhood asthma in the unadjusted analysis (risk ratio [RR] 1.20, 95% confidence interval [CI] 0.78, 1.83) and a 26% increase in risk after adjustment (adjusted RR 1.26, 95% CI 0.79, 2.01). DISCUSSION/SIGNIFICANCE: In our study population, the majority of children with Down syndrome were exposed to antibiotics prenatally and the prevalence of asthma was high. Prenatal antibiotic exposure was associated with an increased risk of childhood asthma among children with Down syndrome; however, this increase was not statistically significant.

Spinal cord injury (SCI) is a catastrophic disease with a complex pathogenesis that includes inflammation, oxidative stress, and glial scar formation. Macrophages are the main mediators of the inflammatory response and are distributed in the epicentre of the SCI. Macrophages have neurotoxic and neuroprotective phenotypes (also known as classically and alternatively activated macrophages or M1 and M2 macrophages) that are associated with pro- or anti- inflammatory gene expression. Our previous study demonstrated that photobiomodulation (PBM) alters the polarization state of macrophages in the SCI region towards the M2 phenotype and promotes the recovery of motor function in rats with SCI. However, the mechanism by which PBM promotes SCI repair remains largely undefined. This study is based on the replacement of conventional percutaneous irradiation with implantable biofibre optic in vivo irradiation. The aim was to further investigate the effects of PBM on SCI in mice under new irradiation patterns and its potential mechanisms of action. PBM was administered to male mice with clamped SCI for four consecutive weeks and significantly promoted the recovery of motor function in mice. Analysis of the macrophage phenotypes in the epicentre of the SCI in mice showed that PBM mainly inhibited the neurotoxic activation of macrophages in the SCI area and reduced the secretion of inflammatory factors such as IL-1α and IL-6; PBM had no effect on M2 macrophages. Immediately afterwards, we constructed in vitro models of the inflammatory polarization of macrophages and PBM intervention. We found that PBM attenuated the neurotoxicity of M1 macrophages on VSC 4.1 motor neurons and dorsal root ganglion (DRG) neurons. The effects of PBM on neurotoxic macrophages and the possible mechanisms of action were analysed using RNA sequencing (RNA-seq), which confirmed that the main role of PBM was to modulate the inflammatory response and immune system processes. Analysis of the differentially expressed genes (DEGs) associated with the inflammatory response showed that PBM had the most significant regulatory effects on genes such as interleukin (IL)-1α, IL-6, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and had obvious inhibitory effects on inflammation-related Notch1 and hypoxia-inducible factor-1α (HIF-1α) pathway genes. RNA-seq analysis of the effect of PBM on gene expression in resting-state macrophages and M2 macrophages did not show significant differences (data not shown). In conclusion, PBM promoted better motor recovery after SCI in mice by inhibiting the neurotoxic polarization of macrophages and the release of inflammatory mediators by acting on the Notch1-HIF-1α/NF-κB Signalling Pathway.

Simple Summary: Lipopolysaccharide (LPS), an endotoxin derived from the outer membrane of Gram-negative bacteria, is one of the causes of acute liver injury. Cordyceps militaris extract (CME) contains many bioactive compounds, mainly cordycepin (CPN). This study aimed to investigate the possible mechanisms underlying the amelioration of LPS-induced acute liver injury in piglets by CME or CPN supplementation using transcriptomic and metabolomic analyses. We found that CPN or CME supplementation significantly decreased the C-reactive protein level and improved liver tissue pathology after LPS injection. Transcriptomic and metabolomic results showed that CME or CPN supplementation could attenuate liver injury by downregulating LPS-induced liver inflammation-related pathways and by modulating the levels of immune response-related metabolites. The present study reveals the immunomodulatory effects of CPN and CME against LPS-induced liver injury. Cordyceps militaris extract (CME) contains many bioactive compounds, mainly cordycepin (CPN). This study aimed to investigate the possible mechanisms underlying the amelioration of LPS-induced acute liver injury in piglets by CME or CPN supplementation using multi-omics analysis. Twenty-four weaned piglets were randomly distributed into 4 groups (n = 6): the control and LPS groups were fed basal diets; the CPN + LPS (CPN-LPS) and CME + LPS (CME-LPS) groups were fed the basal diets supplemented with CME or CPN. The results showed that CPN or CME supplementation significantly decreased the C-reactive protein level (p < 0.05) and improved liver tissue pathology to prevent acute liver injury after LPS treatment. Compared with LPS, the transcriptomic analysis indicated that CPN supplementation significantly downregulated cell adhesion molecules, while CME supplementation significantly downregulated inflammatory mediator regulation of TRP channels, complement and coagulation cascades and cytokine-cytokine receptor interaction. The metabolomic results showed that CPN or CME supplementation significantly reduced disease biomarker of bicyclo-prostaglandin E2, and increased levels of deoxyinosine and 3-hydroxyanthranilic acid (p < 0.05). The combined transcriptome and metabolome helped identify two metabolites PC 34:2 and PC 36:0, which may be associated with the restoration of liver cell morphology. In conclusion, CPN and CME could attenuate LPS-induced acute liver injury by regulating immune-related genes and metabolites. This study elucidates the potential protective mechanism of CPN or CME supplementation against acute liver injury. [ABSTRACT FROM AUTHOR]

Cordycepin is considered a major bioactive component in Cordyceps militaris extract. This study was performed to evaluate the ameliorative effect of Cordyceps militaris extract (CME) and cordycepin (CPN) supplementation on intestinal damage in LPS-challenged piglets. The results showed that CPN or CME supplementation significantly increased the villus height (p < 0.01) and villus height/crypt depth ratio (p < 0.05) in the jejunum and ileum of piglets with LPS-induced intestinal inflammation. Meanwhile, CPN or CME supplementation alleviated oxidative stress and inflammatory responses by reducing the levels of MDA (p < 0.05) and pro-inflammatory cytokines in the serum. Additionally, supplementation with CPN or CME modulated the structure of the intestinal microbiota by enriching short-chain fatty acid-producing bacteria, and increased the level of butyrate (p < 0.05). The RNA-seq results demonstrated that CME or CPN altered the complement and coagulation-cascade-related genes (p < 0.05), including upregulating gene KLKB1 while downregulating the genes CFD, F2RL2, CFB, C4BPA, F7, C4BPB, CFH, C3 and PROS1, which regulate the complement activation involved in inflammatory and immune responses. Correlation analysis further demonstrated the potential relation between the gut microbiota and intestinal inflammation, oxidative stress, and butyrate in piglets. In conclusion, CPN or CME supplementation might inhibit LPS-induced inflammation and oxidative stress by modulating the intestinal microbiota and its metabolite butyrate in piglets. [ABSTRACT FROM AUTHOR]

High-precision electrostatic accelerometer has been widely employed in gravity measurement satellites. Accelerometer can be designed for different resolutions and measurement ranges to adapt to different scientific missions. This paper presents an ultra-high sensitivity 70 g-TM electrostatic accelerometer, designed to achieve an adjustable resolution from 10 − 12 m s − 2 Hz − 1 / 2 to 10 − 10 m s − 2 Hz − 1 / 2 with an optimal resolution of 3.3 × 10 − 12 m s − 2 Hz − 1 / 2 . The in-orbit performance of the 70 g-TM accelerometer was tested on the Tianqin-1 satellite. [ABSTRACT FROM AUTHOR]

Continuous renal replacement therapy (CRRT) is widely used for treating critically-ill patients in the emergency department in China. Anticoagulant therapy is needed to prevent clotting in the extracorporeal circulation during CRRT. Regional citrate anticoagulation (RCA) has been shown to potentially be safer and more effective and is now recommended as the preferred anticoagulant method for CRRT. However, there is still a lack of unified standards for RCA management in the world, and there are many problems in using this method in clinical practice. The Emergency Medical Doctor Branch of the Chinese Medical Doctor Association (CMDA) organized a panel of domestic emergency medicine experts and international experts of CRRT to discuss RCA-related issues, including the advantages and disadvantages of RCA in CRRT anticoagulation, the principle of RCA, parameter settings for RCA, monitoring of RCA (mainly metabolic acid–base disorders), and special issues during RCA. Based on the latest available research evidence as well as the paneled experts' clinical experience, considering the generalizability, suitability, and potential resource utilization, while also balancing clinical advantages and disadvantages, a total of 16 guideline recommendations were formed from the experts' consensus. [ABSTRACT FROM AUTHOR]