Association of Altered Plasma Lipidome with Disease Severity in COVID-19 Patients.

The severity of COVID-19 is linked to an imbalanced immune response. The dysregulated metabolism of small molecules and bioactive lipids has also been associated with disease severity. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyze over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). This is the third publication in a series, and it reports the results of comprehensive lipidome profiling using targeted LC-MS/MS. We identified 1076 lipid features across 25 subclasses, including glycerophospholipids, sterols, glycerolipids, and sphingolipids, among which 531 lipid features were dramatically changed in the plasma of intensive care unit (ICU) patients compared to patients in the ward. Patients in the ICU showed 1.3-57-fold increases in ceramides, (lyso-)glycerophospholipids, diglycerides, triglycerides, and plasmagen phosphoethanolamines, and 1.3-2-fold lower levels of a cyclic lysophosphatidic acid, sphingosine-1-phosphates, sphingomyelins, arachidonic acid-containing phospholipids, lactosylceramide, and cholesterol esters compared to patients in the ward. Specifically, phosphatidylinositols (PIs) showed strong fatty acid saturation-dependent behavior, with saturated fatty acid (SFA)- and monosaturated fatty acid (MUFA)-derived PI decreasing and polystaturated (PUFA)-derived PI increasing. We also found ~4000 significant Spearman correlations between lipids and multiple clinical markers of immune response with |R| ≥ 0.35 and FDR corrected Q < 0.05. Except for lysophosphatidic acid, lysophospholipids were positively associated with the CD4 fraction of T cells, and the cytokines IL-8 and IL-18. In contrast, sphingosine-1-phosphates were negatively correlated with innate immune markers such as CRP and IL-6. Further indications of metabolic changes in moderate COVID-19 disease were demonstrated in recovering ward patients compared to those at the start of hospitalization, where 99 lipid species were altered (6 increased by 30-62%; 93 decreased by 1.3-2.8-fold). Overall, these findings support and expand on early reports that dysregulated lipid metabolism is involved in COVID-19.

Steep Posterior Tibial Slope and Excessive Anterior Tibial Translation Are Associated With Increased Sagittal Meniscal Extrusion After Posterior Lateral Meniscus Root Repair Combined With Anterior Cruciate Ligament Reconstruction.

Purpose: To (1) evaluate the clinical and radiographic outcomes of patients with primary anterior cruciate ligament reconstruction (ACLR) with type II posterior lateral meniscus root tear (PLMRT) repair and (2) identify whether increased anterior tibial subluxation of the lateral compartment (ATSLC) and steeper posterior tibial slope (PTS) are associated with sagittal lateral meniscal extrusion (LME). Methods: Patients who underwent primary anatomic ACLR with concomitant type II PLMRTs using the all-inside side-to-side repair technique between November 2014 and September 2020 were identified. To be included, patients must have had a minimum of 2 years follow-up. All patients, including those with ATSLC and PTS and sagittal and coronal LME, were retrospectively reviewed clinically and radiologically. The patients were divided into 2 subgroups according to the occurrence of sagittal LME. Results: Forty patients were included in this study with a mean follow-up of 44 months (range, 24-94 months). In general, the postoperative parameters, including grade of pivot shift, side-to-side difference, ATSLC, Lysholm score, and International Knee Documentation Committee (IKDC) score, were significantly improved compared with the preoperative ones. However, postoperative sagittal LME was detected to be significantly larger than the preoperative one. Minimal clinically important difference (MCID) analysis for postoperative outcomes showed that the rate of patients who achieved MCID thresholds was 100% for Lysholm, 95% for IKDC, 42.50% for coronal LME, 62.50% for sagittal LME, 40% for ATSLC, and 100% for side-to-side difference. Further comparisons, where patients were divided into 2 subgroups according to the occurrence of sagittal LME, showed significant differences in PTS, ATSLC, and coronal LME. Conclusions: Clinical outcomes after type II PLMRT repair with primary ACLR were significantly improved, except for LME, at the 2-year postoperative follow-up. After repair of type II PLMRT injuries, the presence of sagittal LME was associated with increased PTS and ATSLC. Level of Evidence: Level III, retrospective cohort study.

Synthesis of urolithin derivatives and their anti-inflammatory activity.

Two series of urolithin derivatives, totally 38 compounds, were synthesized. Their anti-inflammatory activity was investigated by detecting the inhibitory effects on the expression of TNF-α in bone marrow-derived macrophages (BMDMs), showing that 24 of 38 ones reduced the expression of TNF-α. Compound B2, the ring C opened derivative of urolithin B with a butoxycarbonyl substitution in ring A, showed the strongest inhibitory activity compared with that of indomethacin. Furthermore, B2 treatment decreased the expression of pro-inflammatory factors IL-1ß, IL-6, iNOS and COX-2. Mechanically, the anti-inflammatory effect of B2 was related to the inhibition of NF-κB signaling pathway. These results clearly illustrated that B2 hold potential for application as an anti-inflammatory agent. The present study provided a viable approach to modify the gut metabolites for anti-inflammatory drug development.

Scavenger Receptor BI Deficiency in Mice Is Associated With Plasma Ceramide and Sphingomyelin Accumulation and a Reduced Cholesteryl Ester Fatty Acid Length and Unsaturation Degree.

Objective: Scavenger receptor class B type I (SR-BI) is primarily known for its role in the selective uptake of cholesteryl esters (CEs) from high-density lipoproteins (HDLs). Here we investigated whether SR-BI deficiency is associated with other potentially relevant changes in the plasma lipidome than the established effect of HDL-cholesterol elevation. Methods: Targeted ultra-high-performance liquid chromatography-tandem mass spectrometry was utilized to measure lipid species in plasma from female wild-type and SR-BI knockout mice. Results: SR-BI deficiency was associated with a reduction in the average CE fatty acid length (-2%; p<0.001) and degree of CE fatty acid unsaturation (-18%; p<0.001) due to a relative shift from longer, polyunsaturated CE species CE (20:4), CE (20:5), and CE (22:6) towards the mono-unsaturated CE (18:1) species. Sphingomyelin (SM) levels were 64% higher (p<0.001) in SR-BI knockout mice without a parallel change in (lyso)phosphatidylcholine (LPC) concentrations, resulting in an increase in the SM/LPC ratio from 0.102±0.005 to 0.163±0.003 (p<0.001). In addition, lower LPC lengths (-5%; p<0.05) and fatty acid unsaturation degrees (-20%; p<0.01) were detected in SR-BI knockout mice. Furthermore, SR-BI deficiency was associated with a 4.7-fold increase (p<0.001) in total plasma ceramide (Cer) levels, with a marked >9-fold rise (p<0.001) in Cer (d18:1/24:1) concentrations. Conclusion: We have shown that SR-BI deficiency in mice not only impacts the CE concentrations, length, and saturation index within the plasma compartment, but is also associated with plasma accumulation of several Cer and SM species that may contribute to the development of specific hematological and metabolic (disease) phenotypes previously detected in SR-BI knockout mice.

ARAP1 negatively regulates stress fibers formation and metastasis in lung adenocarcinoma via controlling Rho signaling.

Small GTPases regulate multiple important cellular behaviors and their activities are strictly controlled by a mass of regulators. The dysfunction or abnormal expression of small GTPases or their regulators was frequently observed in various cancers. Here, we analyzed the expression and prognostic correlation of several GTPases and related regulators based on the TCGA database and found that Ankyrin Repeat and PH Domain 1 (ARAP1), a GTPase activating protein (GAP), is reduced in lung adenocarcinoma tissues compared to normal tissues and displays a positive correlation with overall survival (OS) and progression-free survival (PFS) of patients with lung adenocarcinoma. qPCR and western blot verified that ARAP1 is frequently downregulated in lung adenocarcinoma tumor tissues and cancer cells, and its downregulation might be mediated by epigenetic modification. Moreover, metastatic assays showed that overexpression of ARAP1 significantly inhibits metastasis of lung adenocarcinoma in vitro and in vivo. We further demonstrated that Rho signaling inhibition, mediated by RhoGAP activity of ARAP1, majorly contributes to suppressing migration and invasion of lung adenocarcinoma cancer cells via inhibiting stress fibers formation. In summary, this study indicates that ARAP1 may serve as a potential prognostic predictor and a metastatic suppressor in lung adenocarcinoma via its RhoGAP activity.

A Web-Based Prediction Tool to Improve Identification of Patients With Undersized Hamstring Tendon Autograft in Anterior Cruciate Ligament Reconstruction.

BACKGROUND: An undersized hamstring tendon (HT) autograft is significantly associated with a higher graft failure rate in anterior cruciate ligament reconstruction (ACLR) surgery. The ability to accurately predict inadequate HT graft diameter is critical, as it could assist surgeons in making better graft choices and surgical plans. PURPOSE: To develop a web-based prediction tool to better assess the size of HT autograft and to help clinicians accurately identify patients with potentially undersized HT grafts in order to make appropriate clinical decisions. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 588 patients who received primary arthroscopic single-bundle ACLR surgery with gracilis tendon (GT) and semitendinosus tendon (ST) autograft were retrospectively reviewed. According to the size of 4-strand HT graft, patients were divided into diameter ≥8 mm and <8 mm groups. The least absolute shrinkage and selection operator method and logistic regression were used to identify the independent factors associated with HT graft diameter and establish the models. The prediction performance of the model was evaluated by concordance index and calibration combined with external validation. The diagnostic performance of the prediction model was assessed by sensitivity, specificity, predictive values, and likelihood ratios. Decision curve analysis was used to evaluate the clinical utility of the model. RESULTS: Among the numerous indicators, sex, weight, height, thigh length, and ST-GT diameter (measured on plane 1 of a magnetic resonance imaging scan) were identified to be highly correlated predictors that could provide satisfactory prediction performance in determining the HT graft diameter. Based on these predictors, a prediction model named the HTD model was developed with satisfactory discrimination (concordance index, 0.932) and calibration (mean absolute error, 0.039). When the probability calculated by the HTD model was >65%, the sensitivity and specificity of predicting 4-strand HT graft diameter ≥8 mm were 86.7% and 90.2%, respectively. CONCLUSION: As a useful supplementary prediction tool, the HTD model could accurately predict the diameter of HT autograft during preoperative planning.

Lapachol inhibits the growth of lung cancer by reversing M2-like macrophage polarization via activating NF-κB signaling pathway.

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment (TME) and improve innate and adaptive antitumor immunity. Lapachol, a naturally occurring 1,4-naphthoquinone, exhibits various pharmacological activities including antitumor, anti-leishmanial, antimalarial and antiseptic. In this study, we investigated the relevance of macrophage polarization and the antitumor effect of lapachol in Lewis lung cancer (LLC) both in vitro and in vivo. This study demonstrated that lapachol significantly reversed the polarization of M2-like macrophages thus that were endowed with the ability to kill LLC cells by activating NF-κB signaling pathway. Furthermore, lapachol effectively suppressed tumor growth in C57BL/6 mice bearing lung tumors by reducing the proportion of M2-like macrophages. Overall, our findings clearly illustrated that lapachol could reverse the polarization of M2-like macrophages to improve the immunosuppressive tumor microenvironment, and had the potential to be developed as an immunomodulatory antitumor agent.

Development of a targeted hydrophilic interaction liquid chromatography-tandem mass spectrometry based lipidomics platform applied to a coronavirus disease severity study.

The importance of lipids seen in studies of metabolism, cancer, the recent COVID-19 pandemic and other diseases has brought the field of lipidomics to the forefront of clinical research. Quantitative and comprehensive analysis is required to understand biological interactions among lipid species. However, lipidomic analysis is often challenging due to the various compositional structures, diverse physicochemical properties, and wide dynamic range of concentrations of lipids in biological systems. To study the comprehensive lipidome, a hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS)-based screening method with 1200 lipid features across 19 (sub)classes, including both nonpolar and polar lipids, has been developed. HILIC-MS/MS was selected due to its class separation property and fatty acyl chain level information. 3D models of class chromatographic retention behavior were established and evaluations of cross-class and within-class interferences were performed to avoid over-reporting these features. This targeted HILIC-MS/MS method was fully validated, with acceptable analytical parameters in terms of linearity, precision, reproducibility, and recovery. The accurate quantitation of 608 lipid species in the SRM 1950 NIST plasma was achieved using multi-internal standards per class and post-hoc correction, extending current databases by providing lipid concentrations resolved at fatty acyl chain level. The overall correlation coefficients (R2) of measured concentrations with values from literature range from 0.64 to 0.84. The applicability of the developed targeted lipidomics method was demonstrated by discovering 520 differential lipid features related to COVID-19 severity. This high coverage and targeted approach will aid in future investigations of the lipidome in various disease contexts.

LARAI portal provides a safe method for lateral meniscus repair: three-dimensional computed tomography and cadaveric assessment.

BACKGROUND: Lateral, All-Round and All-Inside (LARAI) portal is a viewing or working portal for observing and repairing the lesions of the lateral meniscus. However, there are safety concerns about popliteal artery (PA) injuries during the procedure. This study aimed to assess the safe distance between the trajectory of the LARAI portal and PA. MATERIALS AND METHODS: Both three-dimensional computed tomography (3D-CT) and cadavers were used to simulate the LARAI portal trajectory. In the 3D-CT study, between January 2020 and September 2020, 45 participants who underwent computed tomography angiography were included in the study. The shortest distance from the PA to the simulated trajectory needle (PS) was measured using 3D-CT. Mean -3SD -2 was calculated to assess the safety of the LARAI portal trajectory. If this value was more than zero, the trajectory was considered "safe." In the cadaveric study, lower limbs from seven fresh-frozen cadavers were used to establish the "safe" trajectories of the LARAI portal, and the PS was measured. RESULTS: In the 3D-CT study, the longest PS (P < 0.001) was found 20 mm lateral to the edge of the patellar tendon trajectory at 0 mm from the posterior cruciate ligament (PCL). Safe trajectories were also found 10 mm, 15 mm, and 20 mm lateral to the edge of the patellar tendon at 0 mm from the PCL, as well as the 20 mm lateral to the edge of the patellar tendon at 3 mm from the PCL. The cadaveric study showed that the average PS of all safe trajectories closely adjoined to PCL was greater than 14 mm. CONCLUSIONS: The LARAI portal trajectory in the "figure of four" is safe, and the optimal insertion point is 10-20 mm lateral to the edge of the patellar tendon and closely adjoined to the posterolateral margin of the PCL at knee joint line level. LEVEL OF EVIDENCE: Level IV.

Local radiotherapy for murine breast cancer increases risk of metastasis by promoting the recruitment of M-MDSCs in lung.

BACKGROUND: Radiotherapy is one of the effective methods for treatment of breast cancer; however, controversies still exist with respect to radiotherapy for patients with TNBC. Here, we intend to explore the mechanism by which local radiotherapy promotes the recruitment of M-MDSCs in the lung and increases the risk of lung metastasis in TNBC tumor-bearing mice. METHODS: A single dose of 20 Gy X-ray was used to locally irradiate the primary tumor of 4T1 tumor-bearing mice. Tumor growth, the number of pulmonary metastatic nodules, and the frequency of MDSCs were monitored in the mice. Antibody microarray and ELISA methods were used to analyze the cytokines in exosomes released by irradiated (IR) or non-IR 4T1 cells. The effects of the exosomes on recruitment of MDSCs and colonization of 4T1 cells in the lung of normal BALB/c mice were observed with the methods of FCM and pathological section staining. T lymphocytes or 4T1 cells co-cultured with MDSCs were performed to demonstrate the inhibitory effect on T lymphocytes or accelerative migration effect on 4T1 cells. Finally, a series of in vitro experiments demonstrated how the exosomes promote the recruitment of M-MDSCs in lung of mice. RESULTS: Even though radiotherapy reduced the burden of primary tumors and larger lung metastatic nodules (≥ 0.4 mm2), the number of smaller metastases (< 0.4 mm2) significantly increased. Consistently, radiotherapy markedly potentiated M-MDSCs and decreased PMN-MDSCs recruitment to lung of tumor-bearing mice. Moreover, the frequency of M-MDSCs of lung was positively correlated with the number of lung metastatic nodules. Further, M-MDSCs markedly inhibited T cell function, while there was no difference between M-MDSCs and PMN-MDSCs in promoting 4T1 cell migration. X-ray irradiation promoted the release of G-CSF, GM-CSF and CXCl1-rich exosomes, and facilitated the migration of M-MDSCs and PMN-MDSCs into the lung through CXCL1/CXCR2 signaling. While irradiated mouse lung extracts or ir/4T1-exo treated macrophage culture medium showed obvious selective chemotaxis to M-MDSCs. Mechanistically, ir/4T1-exo induce macrophage to produce GM-CSF, which further promoted CCL2 release in an autocrine manner to recruit M-MDSCs via CCL2/CCR2 axis. CONCLUSIONS: Our work has identified an undesired effect of radiotherapy that may promote immunosuppressive premetastatic niches formation by recruiting M-MDSCs to lung. Further studies on radiotherapy combined CXCR2 or CCR2 signals inhibitors were necessary.

Optimal fibular tunnel direction for anterior talofibular ligament reconstruction: 45 degrees outperforms 30 and 60 degrees.

PURPOSE: There is currently no consensus on the optimal drilling direction of the fibular bone tunnel for anterior talofibular ligament (ATFL) reconstruction, and few studies have investigated the potential injury to the peroneus longus and brevis tendons and the possibility of fibular fractures during the drilling process. The aim of this study was to assess the potential risk of drilling the tunnel from different directions and determine the most appropriate tunnel direction. The hypothesis was that drilling the tunnel in the 45-degree direction would be the safest and most suitable for the fibular tunnel. METHODS: Forty-eight fibular tunnels were drilled on fresh ankle specimens using a K-wire guide and a 5.0 mm hollow drill. Three tunnel orientations were created, parallel to the sagittal plane of the long axis of the fibula and angled 30°, 45°, and 60° to the coronal plane. The length of the fibular tunnel and the distances from the outlet of the K-wire to the peroneus longus and brevis tendons were measured. The occurrence of a fibula fracture was also observed. RESULTS: The lengths of the bone tunnels in the three groups were 32.9 ± 6.1 mm (30°), 27.2 ± 4.4 mm (45°) and 23.6 ± 4.0 mm (60°). The length of the tunnel drilled at 30° was the longest when compared with that of the tunnels drilled at 45° and 60° (all p values < 0.05). The distances from the outlet of the K-wire to the peroneus longus tendon were 3.0 ± 3.8 mm (30°), 3.8 ± 3.2 mm (45°) and 5.3 ± 1.8 mm (60°), and the distances to the peroneus brevis tendon were 4.2 ± 4.0 mm (30°), 6.1 ± 3.8 mm (45°), 7.9 ± 3.5 mm (60°). In terms of protecting the peroneus longus and brevis tendons, drilling in the 60° direction was better than drilling in the 30° and 45° directions (all p values < 0.05). The risk of injury to the peroneal longus and brevis tendons was 62.5% (30°), 31.3% (45°), and 0% (60°). Although no fibular fractures were observed in any of the three directions, drilling the bone tunnel in the 60° direction disrupted the lateral cortex of the fibula. CONCLUSION: This study shows that drilling the tunnel in the 45° direction is less likely to cause injury to the peroneus longus and brevis tendons, while ensuring that the tunnel has a sufficient length and avoiding fracturing the distal fibula. Drilling a fibular bone tunnel in a 45° direction is safer and recommended for ATFL reconstruction.

Altered methionine-sulfone levels are associated with impaired growth in HIV-exposed-uninfected children.

OBJECTIVE: To determine immune-metabolic dysregulation in children born to women living with HIV. METHODS: Longitudinal immune-metabolomic analyses of plasma of 32 pregnant women with HIV (WHIV) and 12 uninfected women and their children up to 1.5 years of age were performed. RESULTS: Using liquid chromatography-mass spectrometry and a multiplex bead assay, 280 metabolites (57 amino acids, 116 positive lipids, 107 signalling lipids) and 24 immune mediators (e.g. cytokines) were quantified. combinational antiretroviral therapy (cART) exposure was categorized as cART initiation preconception (long), cART initiation postconception up to 4 weeks before birth (medium) and cART initiation within 3 weeks of birth (short). Plasma metabolite profiles differed between HIV-exposed-uninfected (HEU)-children with long cART exposure compared to HIV-unexposed-children (HUU). Specifically, higher levels of methionine-sulfone, which is associated with oxidative stress, were detected in HEU-children with long cART exposure compared to HUU-children. High infant methionine-sulfone levels were reflected by high prenatal plasma levels in the mother. Increased methionine-sulfone levels in the children were associated with decreased growth, including both weight and length. CONCLUSION: These findings based on longitudinal data demonstrate that dysregulation of metabolite networks associated with oxidative stress in children born to WHIV is associated with restricted infant growth.

Metagenomic next-generation sequencing of bronchoalveolar lavage fluid from children with severe pneumonia in pediatric intensive care unit.

Background: Severe pneumonia due to lower respiratory tract infections (LRTIs) is a significant cause of morbidity and mortality in children. Noninfectious respiratory syndromes resembling LRTIs can complicate the diagnosis and may also make targeted therapy difficult because of the difficulty of identifying LRTI pathogens. In the present study, a highly sensitive metagenomic next-generation sequencing (mNGS) approach was used to characterize the microbiome of bronchoalveolar lavage fluid (BALF) in children with severe lower pneumonia and identify pathogenic microorganisms that may cause severe pneumonia. The purpose of this study was to use mNGS to explore the potential microbiomes of children with severe pneumonia in a PICU. Methods: We enrolled patients meeting diagnostic criteria for severe pneumonia admitted at PICU of the Children's Hospital of Fudan University, China, from February 2018 to February 2020. In total, 126 BALF samples were collected, and mNGS was performed at the DNA and/or RNA level. The pathogenic microorganisms in BALF were identified and correlated with serological inflammatory indicators, lymphocyte subtypes, and clinical symptoms. Results: mNGS of BALF identified potentially pathogenic bacteria in children with severe pneumonia in the PICU. An increased BALF bacterial diversity index was positively correlated with serum inflammatory indicators and lymphocyte subtypes. Children with severe pneumonia in the PICU had the potential for coinfection with viruses including Epstein-Barr virus, Cytomegalovirus, and Human betaherpesvirus 6B, the abundance of which was positively correlated with immunodeficiency and pneumonia severity, suggesting that the virus may be reactivated in children in the PICU. There was also the potential for coinfection with fungal pathogens including Pneumocystis jirovecii and Aspergillus fumigatus in children with severe pneumonia in the PICU, and an increase in potentially pathogenic eukaryotic diversity in BALF was positively associated with the occurrence of death and sepsis. Conclusions: mNGS can be used for clinical microbiological testing of BALF samples from children in the PICU. Bacterial combined with viral or fungal infections may be present in the BALF of patients with severe pneumonia in the PICU. Viral or fungal infections are associated with greater disease severity and death.

Repairing Avascular Meniscal Lesions by Recruiting Endogenous Targeted Cells Through Bispecific Synovial-Meniscal Aptamers.

BACKGROUND: Tissue engineering is a promising treatment option for meniscal lesions in the avascular area, but a favorable cell source and its utilization in tissue-engineered menisci remain uncertain. Therefore, a more controllable and convenient method for cell recruitment is required. HYPOTHESIS: Circular bispecific synovial-meniscal (S-M) aptamers with a gelatin methacryloyl (GelMA) hydrogel can recruit endogenous synovial and meniscal cells to the site of the defect, thereby promoting in situ meniscal regeneration and chondroprotection. STUDY DESIGN: Controlled laboratory study. METHODS: Synovial and meniscal aptamers were filtered through systematic evolution of ligands by exponential enrichment (SELEX) and cross-linked to synthesize the S-M aptamer. A GelMA-aptamer system was constructed. An in vitro analysis of the bi-recruitment of synovial and meniscal cells was performed, and the migration and proliferation of the GelMA-aptamer hydrogel were also tested. For the in vivo assay, rabbits (n = 90) with meniscal defects in the avascular zone were divided into 3 groups: repair with the GelMA-aptamer hydrogel (GelMA-aptamer group), repair with the GelMA hydrogel (GelMA group), and no repair (blank group). Regeneration of the repaired meniscus and degeneration of the cartilage were assessed by gross and histological evaluations at 4, 8, and 12 weeks postoperatively. The mechanical properties of repaired menisci were also evaluated. RESULTS: In vitro synovial and meniscal cells were recruited simultaneously by the S-M aptamer with high affiliation and specificity. The GelMA-aptamer hydrogel promoted the migration of targeted cells. Compared with the other groups, the GelMA-aptamer group showed enhanced fibrocartilaginous regeneration, lower cartilage degeneration, and better mechanical strength at 12 weeks after meniscal repair. CONCLUSION/CLINICAL RELEVANCE: Bispecific S-M aptamers could be used for avascular meniscal repair by recruiting endogenous synovial and meniscal cells and promoting fibrocartilaginous regeneration.

Development of Neuropeptide Hemokinin-1 Analogues with Antimicrobial and Wound-Healing Activity.

Wound healing is a complex process that can be delayed in some pathological conditions, such as infection and diabetes. Following skin injury, the neuropeptide substance P (SP) is released from peripheral neurons to promote wound healing by multiple mechanisms. Human hemokinin-1 (hHK-1) has been identified as an SP-like tachykinin peptide. Surprisingly, hHK-1 shares similar structural features with antimicrobial peptides (AMPs), but it does not display efficient antimicrobial activity. Therefore, a series of hHK-1 analogues were designed and synthesized. Among these analogues, AH-4 was found to display the greatest antimicrobial activity against a broad spectrum of bacteria. Furthermore, AH-4 rapidly killed bacteria by membrane disruption, similar to most AMPs. More importantly, AH-4 showed favorable healing activity in all tested mouse full-thickness excisional wound models. Overall, this study suggests that the neuropeptide hHK-1 can be used as a desirable template for developing promising therapeutics with multiple functions for wound healing.

Chinese Experts Consensus and Practice Guideline on Discoid Lateral Meniscus.

Discoid lateral meniscus (DLM) is the most common congenital variant of the lateral meniscus, which is prone to degeneration and lesions, and often leads to knee osteoarthritis. At present, there is no consensus on the clinical practice of DLM, and this expert consensus and practice guidelines on DLM was developed and approved by Chinese Society of Sports Medicine according to the Delphi method. Among 32 statements drafted, 14 statements were excluded for redundant information, and 18 statements achieved consensus. This expert consensus focused on the definition, epidemiology, etiology, classification, clinical manifestations, diagnosis, treatment, prognosis, and rehabilitation of DLM. Restoring the normal shape, retaining appropriate width and thickness, and ensuring the stability of the remnant meniscus is critical to sustaining the physiological function of the meniscus and preserving the knee. The partial meniscectomy with or without repair should be the first-line treatment when possible, given that the clinical and radiological long-term outcomes of total or subtotal meniscectomy are worse.

RRP15 deficiency induces ribosome stress to inhibit colorectal cancer proliferation and metastasis via LZTS2-mediated ß-catenin suppression.

Ribosome biogenesis (RiBi) plays a pivotal role in carcinogenesis by regulating protein translation and stress response. Here, we find that RRP15, a nucleolar protein critical for RiBi and checkpoint control, is frequently upregulated in primary CRCs and higher RRP15 expression positively correlated with TNM stage (P < 0.0001) and poor survival of CRC patients (P = 0.0011). Functionally, silencing RRP15 induces ribosome stress, cell cycle arrest, and apoptosis, resulting in suppression of cell proliferation and metastasis. Overexpression of RRP15 promotes cell proliferation and metastasis. Mechanistically, ribosome stress induced by RRP15 deficiency facilitates translation of TOP mRNA LZTS2 (Leucine zipper tumor suppressor 2), leading to the nuclear export and degradation of ß-catenin to suppress Wnt/ß-catenin signaling in CRC. In conclusion, ribosome stress induced by RRP15 deficiency inhibits CRC cell proliferation and metastasis via suppressing the Wnt/ß-catenin pathway, suggesting a potential new target in high-RiBi CRC patients.

Clinical characteristics and outcomes of children with prolonged mechanical ventilation in PICUs in mainland China: A national survey.

OBJECTIVE: The number of children on prolonged mechanical ventilation (PMV) in pediatric intensive care units (PICU) has increased markedly, but little is known about the situation in mainland China. We carried out a multicenter retrospective investigation to describe the clinical characteristics and prognosis of Chinese children receiving long-term ventilation in the PICU. METHODS: A retrospective study was performed in 11 PICUs. All participating patients with prolonged mechanical ventilation in the study were retrospectively identified and included from cases admitted to PICUs between January 1, 2017 and December 31, 2019. RESULTS: A total of 346 children diagnosed with prolonged mechanical ventilation were included in the study. Overall, 240 survived and were discharged from PICU, 55 died in hospital, and 51 withdrew from mechanical ventilation support with 41 died after discharge. Lower airway diseases were the most common underlying causes (41.6%), followed by central nervous system diseases (29.5%), and neuromuscular diseases (13.3%). Most children (327, 94.5%) received invasive mechanical ventilation (IMV) and only 19 (5.5%) children received noninvasive ventilation (NIV). The median time of tracheostomy after ventilation was 21 days (15-35). Children with tracheostomy had lower mortality with longer PICU stay compared with patients without tracheostomy. Children who underwent tracheostomy were more likely to have central nervous system diseases and neuromuscular diseases. CONCLUSION: This study showed a steady increase in the number of children receiving prolonged mechanical ventilation during the study period in Chinese PICUs with distinct clinical characteristics and outcomes. A better community-based care for PMV children is needed in mainland China.

The Prevalence and Characteristics of Chronic Ankle Instability in Elite Athletes of Different Sports: A Cross-Sectional Study.

BACKGROUND: Ankle sprains are one of the most common injuries in athletic populations. Misdiagnosed and untreated ankle sprains will cause chronic ankle instability (CAI), which can significantly affect the performance of athletes. This study aimed to investigate the prevalence and characteristics of CAI in elite athletes of different sports. METHOD: This cross-sectional study included 198 elite athletes from Guangdong provincial sports teams. All participants answered a questionnaire about ankle sprains and ankle instability. The severity of their ankle instability was evaluated by the Cumberland Ankle Instability Tool (CAIT). Participants further underwent clinical examinations from sports medicine doctors to determine the presence and characteristics of ankle instability. The datasets were analyzed to determine the differences in prevalence between age, gender, sports teams, and sports categories. RESULTS: In 198 athletes, 39.4% (n = 78) had bilateral CAI while 25.3% (n = 50) had unilateral CAI. Female athletes had a higher prevalence of CAI than male athletes in the study (p = 0.01). Prevalence showed differences between sports categories, and were significantly higher in acrobatic athletes than non-contact athletes (p = 0.03). CONCLUSIONS: CAI was highly prevalent among elite athletes in this study, with female athletes and athletes in acrobatic sports being associated with a higher risk of developing CAI in their professional careers. Therefore, extra precautions need to be taken into account when applying ankle protections for these athletes.