Electrically empowered microcomb laser.

Optical microcomb underpins a wide range of applications from communication, metrology, to sensing. Although extensively explored in recent years, challenges remain in key aspects of microcomb such as complex soliton initialization, low power efficiency, and limited comb reconfigurability. Here we present an on-chip microcomb laser to address these key challenges. Realized with integration between III and V gain chip and a thin-film lithium niobate (TFLN) photonic integrated circuit (PIC), the laser directly emits mode-locked microcomb on demand with robust turnkey operation inherently built in, with individual comb linewidth down to 600 Hz, whole-comb frequency tuning rate exceeding 2.4 × 1017 Hz/s, and 100% utilization of optical power fully contributing to comb generation. The demonstrated approach unifies architecture and operation simplicity, electro-optic reconfigurability, high-speed tunability, and multifunctional capability enabled by TFLN PIC, opening up a great avenue towards on-demand generation of mode-locked microcomb that is of great potential for broad applications.

Optimizing enzyme properties to enhance dihydroxyacetone production via methylglyoxal biosensor development.

BACKGROUND: Dihydroxyacetone (DHA) stands as a crucial chemical material extensively utilized in the cosmetics industry. DHA production through the dephosphorylation of dihydroxyacetone phosphate, an intermediate product of the glycolysis pathway in Escherichia coli, presents a prospective alternative for industrial production. However, insights into the pivotal enzyme, dihydroxyacetone phosphate dephosphorylase (HdpA), remain limited for informed engineering. Consequently, the development of an efficient tool for high-throughput screening of HdpA hypermutants becomes imperative. RESULTS: This study introduces a methylglyoxal biosensor, based on the formaldehyde-responding regulator FrmR, for the selection of HdpA. Initial modifications involved the insertion of the FrmR binding site upstream of the -35 region and into the spacer region between the -10 and -35 regions of the constitutive promoter J23110. Although the hybrid promoter retained constitutive expression, expression of FrmR led to complete repression. The addition of 350 µM methylglyoxal promptly alleviated FrmR inhibition, enhancing promoter activity by more than 40-fold. The methylglyoxal biosensor system exhibited a gradual increase in fluorescence intensity with methylglyoxal concentrations ranging from 10 to 500 µM. Notably, the biosensor system responded to methylglyoxal spontaneously converted from added DHA, facilitating the separation of DHA producing and non-producing strains through flow cytometry sorting. Subsequently, the methylglyoxal biosensor was successfully applied to screen a library of HdpA mutants, identifying two strains harboring specific mutants 267G > T and D110G/G151C that showed improved DHA production by 68% and 114%, respectively. Expressing of these two HdpA mutants directly in a DHA-producing strain also increased DHA production from 1.45 to 1.92 and 2.29 g/L, respectively, demonstrating the enhanced enzyme properties of the HdpA mutants. CONCLUSIONS: The methylglyoxal biosensor offers a novel strategy for constructing genetically encoded biosensors and serves as a robust platform for indirectly determining DHA levels by responding to methylglyoxal. This property enables efficiently screening of HdpA hypermutants to enhance DHA production.

The Combined Intraosseous Administration of Orthobiologics Outperformed Isolated Intra-articular Injections in Alleviating Pain and Cartilage Degeneration in a Rat Model of MIA-Induced Knee Osteoarthritis.

BACKGROUND: Intra-articular (IA) platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) injections have shown efficacy and safety in treating osteoarthritis (OA). However, the effectiveness and mechanisms of combined intraosseous (IO) administration of these orthobiologics have yet to be explored. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate the effect on pain, cartilage, synovium/infrapatellar fat pad (IFP), and subchondral bone in rat knee OA, comparing isolated IA with combined IA and IO (IA+IO) injections of PRP or BMAC. It was hypothesized that combined injections would be superior to sole IA injections. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 48 rats were divided into 6 groups: sham (only joint puncture during OA induction with IA+IO saline injection treatment) and 5 groups with OA induction, control (IA+IO saline injection), PRP (IA PRP+IO saline injection), BMAC IA (IA BMAC+IO saline injection), PRP IA+IO (IA+IO PRP injection), and BMAC IA+IO (IA+IO BMAC injection). OA was induced by IA injection of monosodium iodoacetate (MIA). Rats were administered different orthobiologics according to their grouping 3 weeks after the MIA injection. Pain changes were evaluated using the weightbearing ratio assay at weeks 3, 4, 5, 7, and 9 after OA induction. Rats were euthanized at week 9 for gross, radiological, histological, immunohistochemical, and immunofluorescence assessments of cartilage, synovium, and subchondral bone. RESULTS: Compared with the control group, all orthobiologics injection groups had reduced joint pain. Compared with IA injection, IA+IO injections provided superior pain relief by suppressing calcitonin gene-related peptide and substance P in both the synovium/IFP and subchondral bone. IA+IO injections slowed the progression of subchondral bone lesions by inhibiting CD31hiEmcnhi vessel formation and excessive osteoclast and osteoblast turnover while preserving subchondral bone microarchitecture, slowing cartilage degeneration. However, IA+IO injections did not outperform isolated IA injections in reducing synovitis and synovium/IFP fibrosis. Compared with PRP, BMAC exhibited superior inhibition of pain-related mediators, but no significant differences were observed in synovitis suppression, infrapatellar fat pad fibrosis, and subchondral bone protection. CONCLUSION: IA+IO injections of orthobiologics were more effective in relieving pain, slowing cartilage degeneration, and inhibiting abnormal vascularization and remodeling compared with isolated IA injections. BMAC showed superior pain relief in the synovium/IFP and subchondral bone compared with PRP. Further research is needed to optimize PRP and BMAC components for enhanced efficacy in OA management. CLINICAL RELEVANCE: Our findings contribute to advancing the understanding of pain relief mechanisms and support the endorsement of IO injection of orthobiologics for the treatment of OA and joint pain.

Acute toxicity of cerium to neonatal Daphnia magna: Responses of antioxidant systems, influence of environmental factors and development of a biotic ligand model.

The bioavailability of cerium (Ce) and its toxic effects on aquatic organisms are still unclear, which limits the toxicity prediction and pollution control for this element. Here, the acute toxicity of Ce to Daphnia magna neonates and the responses of the antioxidant system were investigated, and the quantitative relationships between the toxicity of Ce and environmental factors were determined. The 24 and 48 h EC50Ce-D values based on the dissolved concentration of Ce in Daphnia magna were 60.6 and 10.9 µM, respectively, and the EC50Ce3+ values were 23.4 and 3.73 µM, respectively. After Ce exposure at environmentally relevant concentrations (0.5-3.5 µM), significant increases in superoxide dismutase activity and malondialdehyde content were observed in Daphnia magna, while significant decreases in catalase activity and H2O2 content occurred. Low levels of Ce cause oxidative damage to Daphnia magna and adverse impacts on the antioxidant system; however, further molecular-based studies are needed. The addition of Ca2+ or Na+ reduced the acute toxicity of Ce to Daphnia magna. In contrast, Mg2+ (MgSO4) promoted Ce toxicity, which is a new finding related to the interaction effects between cations and rare earth elements on biological ligands; however, the effects of SO42+ could not be distinguished. Complexation with organic ligands could significantly reduce the toxicity of Ce to Daphnia magna; however, complexes of Ce with citric acid and malic acid might be bioavailable to Daphnia magna. In the absence of organic ligands and competing metals, the binding constant of Ce3+ to Daphnia magna at toxic concentrations was 5.83. The log K values for the competitive effects of Ca2+ and Na+ were 3.73 and 2.59, respectively, while the log K value for the protective effect of fulvic acid was 3.76. These results contribute to understanding the toxicity of Ce and will help predict the toxicity of Ce in freshwater.

The accuracy of multiple regression models for predicting the individual risk of recurrent lateral patellar dislocation.

BACKGROUND: Recurrent lateral patellar dislocation (RLPD) poses a significant threat to patients' quality of life due to knee pain, patellofemoral cartilage damage, and potential traumatic arthritis. Predictive scoring systems have been developed to assess the risk of RLPD; however, their relative accuracy remains uncertain. PURPOSE: To investigate the accuracy of the multiple regression models to predict the individual risk of recurrent LPD. METHODS: The Patellar Instability probability calculator (PIP), Recurrent Instability of the Patella Score (RIP), and Patellar Instability Severity Score (PIS) scoring rules were measured in 171 patients with a history of patellar dislocation and 171 healthy individuals. Three prediction models were calculated based on the data to predict the risk of recurrent lateral patellar dislocation. The inter-observer and intra-observer reliability of each measurement parameter was evaluated. The predictive capacity of the three-prediction model was investigated using the receiver operating characteristic curve. RESULTS: In the case group of 171 patients, PIS accurately predicted recurrent lateral Patella dislocation in 143 patients. RIP was 96, and PIP was 83. The positive predictive values were 92.9%, 64%, and 68% respectively. In the control group of 171 patients, the PIS was validated in 160 patients who would not experience dislocations. RIP was 117, and PIP was 50. The negative predictive values were 85.1%, 60.9%, and 36.2%, respectively. The area under the curve score for the PIS was 0.866, and the RIP was 0.673. the PIP was 0.678. CONCLUSION: RIP and PIP did not work to predict LPD. PIS can accurately predict recurrent lateral patellar dislocation. It can aid doctors in making treatment decisions. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Donor-Matched Peripheral Blood-Derived Mesenchymal Stem Cells Combined With Platelet-Rich Plasma Synergistically Ameliorate Surgery-Induced Osteoarthritis in Rabbits: An In Vitro and In Vivo Study.

BACKGROUND: Osteoarthritis (OA) is a common disease that causes joint pain and disability. Stem cell therapy is emerging as a promising treatment for OA. PURPOSE: To evaluate the ability of peripheral blood-derived mesenchymal stem cells (PBMSCs) combined with donor-matched platelet-rich plasma (PRP) to treat OA in a rabbit model. STUDY DESIGN: Controlled laboratory study. METHODS: PBMSCs and donor-matched PRP were isolated and prepared from the same rabbit. PBMSCs were treated with serum-free medium, fetal bovine serum, and PRP; a series of PBMSC behaviors, including proliferation, migration, and adhesion, were compared among groups. The ability of PBMSCs or PRP alone and PBMSCs+PRP to protect chondrocytes against proinflammatory cytokine (interleukin 1ß [IL-1ß]) treatment was compared by analyzing reactive oxygen species (ROS)-scavenging ability and apoptosis. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate the expression of extracellular matrix (ECM) metabolism genes and proteins, and Western blotting was used to explore the potential mechanism of the corresponding signaling pathway. In vivo, the effect of PBMSCs+PRP on cartilage and inflammation of the synovium was observed in a surgery-induced OA rabbit model via gross observation, histological and immunohistochemical staining, and enzyme-linked immunosorbent assay. RESULTS: Proliferation, migration, and adhesion ability were enhanced in PBMSCs treated with PRP. Moreover, compared with either PBMSCs or PRP alone, PBMSCs+PRP enhanced ROS-scavenging ability and inhibited apoptosis in IL-1ß-treated chondrocytes. PBMSCs+PRP also reversed the IL-1ß-induced degradation of collagen type 2 and aggrecan and increased expression of matrix metalloproteinase 13, and this effect was related to increased expression of ECM synthesis and decreased expression of degradation and inflammatory genes and proteins. Mechanistically, PBMSCs+PRP reduced the phosphorylation of inhibitor of nuclear factor-κBα (IκBα), which further inhibited the phosphorylation of downstream nuclear factor-κB (NF-κB) in the NF-κB signaling pathway. In vivo, compared with PBMSCs or PRP alone, intra-articular (IA) injection of PBMSCs+PRP enhanced cartilage regeneration and attenuated synovial inflammation in OA-induced rabbits. CONCLUSION: These results demonstrate that PRP could enhance biological activities, including viability, migration, and adhesion, in PBMSCs. PBMSCs+PRP could rescue ECM degeneration by inhibiting inflammatory signaling in IL-1ß-treated OA chondrocytes. In addition, IA injection of PBMSCs+PRP effectively attenuated OA progression in a surgery-induced OA rabbit model. CLINICAL RELEVANCE: PBMSCs+PRP may provide a promising treatment for knee OA, and this study can advance the related basic research.

Molecular Mechanism of Bai-Bo Formula for Treatment of Vitiligo Based on Network Pharmacology and Molecular Docking.

Using network pharmacology and molecular docking, this study aims to evaluate the pharmacological mechanism of Bai-Bo Formula in the prevention and treatment of vitiligo. The chemical composition collection and anticipated targets for Bai-Bo Formula for vitiligo were compiled using TCMSP and BATMAN-TCM databases. GeneCards, OMIM, and DisGeNET databases were used to extract targets associated with vitiligo. The acquired drug-component targets were intersected with the illness targets to identify common genes, and a drug-component-target network was created using Cytoscape 3.7.2. Protein-protein interactions of Bai-Bo Formula were examined using String, and function enrichment analyses were performed on the primary targets using gene ontology and the Kyoto encyclopaedia of genes and genomes. Finally, molecular docking technologies were used to validate the combination of primary components and key targets. A study evaluated 167 active ingredients and 1425 prediction targets in 12 traditional Chinese remedies known as Bai-Bo Formula for treating vitiligo. 169 target genes were found to interact with the medicine. The protein-protein interaction network analysis identified 91 important proteins, with the top 5 targets being IL6, TNF, AKT1, IL1, and STAT. Bai-Bo Formula regulates immune inflammation, apoptosis, and autophagy via various pathways, including AGE-RAGE, PI3K-Akt, and TNF signaling. Molecular docking indicated that the primary components could attach effectively to the target protein. Based on network pharmacology and molecular docking, the mechanism of Bai-Bo Formula in the treatment of vitiligo via multicomponent, multitarget, and multichannel was investigated in depth.

Tibial Tubercle-Trochlear Groove Distance Has Better Diagnostic Reliability Than Tubercle-Posterior Cruciate Ligament Distance For Predicting Patellar Instability: A Systematic Review.

OBJECTIVE: The tibial tubercle-trochlear groove (TT-TG) distance is now routinely utilized to help determine whether a realignment procedure is necessary for patients with patellar instability. The tibial tubercle-posterior cruciate ligament (TT-PCL) distance has been explored as an alternative measurement. The aim of this study is to compare the reliability of TT-TG and TT-PCL; to explore whether there is a relationship between the TT-PCL and the TT-TG distance; to determine whether there is a relationship between the TT-TG and TT-PCL distances and knee rotation; and to compare the abilities of the TT-PCL distance and the TT-TG distance with predicted patellar instability. METHOD: This systematic review was performed in accordance with PRISMA guidelines. Three databases, PubMed, EMBASE, and Cochrane Central Register of Controlled Trials, were searched from inception to September 2021 to identify clinical studies comparing TT-TG and TT-PCL distances to patellar instability. Data on patient baseline characteristics, TT-TG and TT-PCL distances, inter-observer reliability, and area under the receiver-operating characteristic curve (AUC) were recorded. The methodological quality of the studies was assessed using the quality assessment form recommended by the Agency for Healthcare Research and Quality (AHRQ). RESULT: Twenty studies were included in the final analysis, comprising 2330 knees from 2260 patients. The current study showed that TT-TG and TT-PCL have similar observer reliability. The inter- and intra-observer reliability of TT-TG ranged from 0.807 to 0.98 and 0.553 to 0.99, respectively. The inter- and intra-observer reliability of TT-PCL ranged from 0.553 to 0.99 and 0.88 to 0.981, respectively. Six studies compared the AUC for predicting patellar instability and showed that TT-TG had better predictive performance than TT-PCL. Three studies reported a correlation between TT-TG and knee rotation, but no such relationship was found for TT-PCL. Eight studies reported a weak or moderate correlation between TT-TG and TT-PCL. CONCLUSION: TT-TG and TT-PCL have similar inter- and intra-rater reliability (as measured by ICC), but TT-TG has greater discriminatory power to predict patellar instability than TT-PCL (as measured by AUC values and odds ratio). However, considering trochlear dysplasia and individual variations, future studies need to find more accurate and individualized methods to predict patellar instability.

[A comparative study of absorbable screw fixation and absorbable screw combined with suture anchor fixation in treatment of avulsion fracture of posterior cruciate ligament at tibial insertion of knee joint].

Objective: To compare the effectiveness of open reduction of posterior cruciate ligament (PCL) avulsion fracture at tibial insertion of knee joint with absorbable screws fixation and absorbable screw combined with suture anchor fixation. Methods: The clinical data of 26 patients with PCL avulsion fracture at tibial insertion who met the selection criteria between March 2015 and October 2021 were retrospectively analyzed. Among them, 14 patients were fixed with simple absorbable screw (group A), and 12 patients were fixed with absorbable screw combined with suture anchors (group B). All patients were confirmed by X-ray film, CT, or MRI preoperatively, and got positive results in preoperative posterior drawer tests. There was no significant difference in gender, age, side of affected limb, time from injury to operation, comorbidities, and preoperative Meyers & McKeever classification, Lysholm score, and International Knee Documentation Committee (IKDC) score between the two groups ( P>0.05). The operation time and postoperative complications were recorded and compared between the two groups. At last follow-up, Lysholm score and IKDC score were used to evaluate the improvement of knee function. Results: There was no significant difference in operation time between the two groups ( P>0.05). All incisions healed by first intention, and no complication such as vascular and nerve injury or venous thrombosis occurred. All 26 patients were followed up 9-89 months, with an average of 55.3 months. The follow-up time of group A and group B was (55.7±23.2) and (56.8±29.3) months, respectively, with no significant difference ( t=-0.106, P=0.916). Radiographs showed bone healing in both groups at 3 months after operation, and no complication such as infection and traumatic arthritis occurred. At last follow-up, the posterior drawer test was negative in both groups, and the Lysholm score and IKDC score significantly improved when compared with the pre-operative values ( P<0.05). However, there was no significant difference in the improvement value between the two groups ( P>0.05). Conclusion: For PCL avulsion fracture at tibial insertion of the knee joint, the open reduction and absorbable screw combined with suture anchor fixation can achieve reliable fracture reduction and fixation, which is conducive to the early rehabilitation and functional exercise, and the postoperative functional recovery of the knee joint is satisfactory.

Input-Constrained Hybrid Control of a Hyper-Redundant Mobile Medical Manipulator.

To reduce the risk of infection in medical personnel working in infectious-disease areas, we proposed a hyper-redundant mobile medical manipulator (HRMMM) to perform contact tasks in place of healthcare workers. A kinematics-based tracking algorithm was designed to obtain highly accurate pose tracking. A kinematic model of the HRMMM was established and its global Jacobian matrix was deduced. An expression of the tracking error based on the Rodrigues rotation formula was designed, and the relationship between tracking errors and gripper velocities was derived to ensure accurate object tracking. Considering the input constraints of the physical system, a joint-constraint model of the HRMMM was established, and the variable-substitution method was used to transform asymmetric constraints to symmetric constraints. All constraints were normalized by dividing by their maximum values. A hybrid controller based on pseudo-inverse (PI) and quadratic programming (QP) was designed to satisfy the real-time motion-control requirements in medical events. The PI method was used when there was no input saturation, and the QP method was used when saturation occurred. A quadratic performance index was designed to ensure smooth switching between PI and QP. The simulation results showed that the HRMMM could approach the target pose with a smooth motion trajectory, while meeting different types of input constraints.

Transtibial Versus Anteromedial Portal Technique for Femoral Tunnel Drilling in Primary Single-Bundle Anterior Cruciate Ligament Reconstruction: A Meta-analysis of Level 1 and 2 Evidence of Clinical, Revision, and Radiological Outcomes.

BACKGROUND: Although numerous clinical studies have compared transtibial (TT) and anteromedial portal (AMP) drilling of femoral tunnels during anterior cruciate ligament reconstruction (ACLR), there is no high-quality, evidence-based consensus regarding which technique affords the best outcome. HYPOTHESIS: There would be no difference between the TT and AMP techniques in terms of knee stability, patient-reported outcomes, incidence of revision, and radiological results. STUDY DESIGN: Meta-analysis; Level of evidence, 2. METHODS: The PubMed and EMBASE databases were searched from inception to February 1, 2021. Level 1 and 2 clinical trials that compared TT and AM techniques were included. Data were meta-analyzed for the outcome measures of knee stability, patient-reported functional outcomes, incidence of revision, and radiological results. Dichotomous variables were presented as odds ratios (ORs), and continuous variables were presented as mean differences (MDs) and standard mean differences (SMDs). RESULTS: The meta-analysis included 18 clinical studies, level of evidence 1 or 2, that involved 53,888 patients. Pooled data showed that the AMP group had a lower side-to-side difference (SMD, 0.22; 95% CI, 0.06 to 0.39; P = .009), a lower incidence of pivot-shift phenomenon (OR, 3.69; 95% CI, 1.26 to 10.79; P = .02), and a higher postoperative Lysholm score (SMD, -0.26; 95% CI, -0.44 to -0.08; P = .005) than the TT group. However, no statistically significant differences were seen in other outcomes, including subjective International Knee Documentation Committee scores (SMD, -0.11; 95% CI, -0.30 to 0.09; P = .30) or grades (OR, 0.93; 95% CI, 0.35 to 2.49; P = .89), postoperative activity level (MD, -0.14; 95% CI, -0.42 to 0.15; P = .35), and incidence of revision ACLR (OR, 1.04; 95% CI, 0.93 to 1.16; P = .45). The TT technique was more likely to create longer (SMD, 1.05; 95% CI, 0.05 to 2.06; P = .04) and more oblique (SMD, 0.81; 95% CI, 0.51 to 1.11; P < .001) femoral tunnels than the AMP technique, and a higher height ratio of the aperture position was detected with the TT technique (SMD, -3.51; 95% CI, -5.54 to -1.49; P < .001). CONCLUSION: The AMP technique for ACLR may be more likely to produce better knee stability and improved clinical outcomes than the TT technique, but no difference was found in the incidence of revision between the 2 groups.

Does Accelerated Rehabilitation Provide Better Outcomes Than Restricted Rehabilitation in Postarthroscopic Repair of Meniscal Injury?

CONTEXT: Meniscal injury is a common pathology, and the postoperative rehabilitation program is essential to patients after surgery. However, the optimal rehabilitation plan after meniscus suture is still controversial. OBJECTIVE: To compare the clinical outcomes between accelerated rehabilitation and restricted programs in patients with meniscus suture (with or without anterior cruciate ligament reconstruction, ACLR). EVIDENCE ACQUISITION: Four databases, including PubMed, Ovid, Embase, and the Cochrane Library, were searched up to November 2021. This study only included studies comparing the clinical outcomes between accelerated (immediate range of motion and weight-bearing) and restricted rehabilitation (immobilization and progressive weight-bearing) for meniscus suture. All selected studies were divided into 2 subgroups: isolated meniscus suture or combined with ACLR. The Lysholm score, Tegner score, and Knee Injury and Osteoarthritis Outcome Score were evaluated in simple meniscus sutures no less than 1 year. Failure rate was evaluated in both groups, and the tunnel enlargement was additionally evaluated in patients who underwent ACLR. EVIDENCE SYNTHESIS: Eleven studies with 612 patients were eligible for analysis. The accelerated group included 4 studies with 330 participants, while the restricted group included 7 studies with 282 participants. For the patients after isolated meniscus suture, the accelerated group achieved higher Lysholm scores (mean difference = -4.66; 95% confidence interval, -8.6 to -0.73; P = .02; I2 = 88%) than the restricted group. For the patients after meniscus suture with ACLR, patients undergoing accelerated rehabilitation were associated with a significantly larger tibial tunnel enlargement in the anterior-posterior view (mean difference = -7.08; 95% confidence interval, -10.92 to -3.24; P = .0003; I2 = 0%) and lateral view (mean difference = -10.33; 95% confidence interval, -16.9 to -3.75; P = .002; I2 = 17%). CONCLUSION: This meta-analysis evaluated the effects of postoperative rehabilitation in either accelerated or restricted programs in patients with meniscus lesions after repair. A significant higher mean self-reported function was discovered at final follow-ups in the accelerated group. However, a significant increase in tibial tunnel enlargement was also found in accelerated group.

A c-Fos activation map in nitroglycerin/levcromakalim-induced models of migraine.

BACKGROUND: Chronic migraine is a common and highly disabling disorder. Functional MRI has indicated that abnormal brain region activation is linked with chronic migraine. Drugs targeting the calcitonin gene-related peptide (CGRP) or its receptor have been reported to be efficient for treating chronic migraine. The CGRP signaling was also shared in two types of chronic migraine models (CMMs). However, it remains unclear whether the activation of specific brain regions could contribute to persistent behavioral sensitization, and CGRP receptor antagonists relieve migraine-like pain in CMMs by altering specific brain region activation. Therefore, it's of great interest to investigate brain activation pattern and the effect of olcegepant (a CGRP receptor-specific antagonist) treatment on alleviating hyperalgesia by altering brain activation in two CMMs, and provide a reference for future research on neural circuits. METHODS: Repeated administration of nitroglycerin (NTG) or levcromakalim (LEV) was conducted to stimulate human migraine-like pain and establish two types of CMMs in mice. Mechanical hypersensitivity was evaluated by using the von Frey filament test. Then, we evaluated the activation of different brain regions with c-Fos and NeuN staining. Olcegepant was administered to explore its effect on mechanical hyperalgesia and brain region activation. RESULTS: In two CMMs, acute and basal mechanical hyperalgesia was observed, and olcegepant alleviated mechanical hyperalgesia. In the NTG-induced CMM, the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and the caudal part of the spinal trigeminal nucleus (Sp5c) showed a significant increase of c-Fos expression in the NTG group (p < 0.05), while pre-treatment with olcegepant reduced c-Fos expression compared with NTG group (p < 0.05). No significant difference of c-Fos expression was found in the paraventricular thalamic nucleus (PVT) and ventrolateral periaqueductal gray (vlPAG) between the vehicle control and NTG group (p > 0.05). In the LEV-induced CMM, mPFC, PVT, and Sp5c showed a significant increase of c-Fos expression between vehicle control and LEV group, and olcegepant reduced c-Fos expression (p < 0.05). No significant difference in c-Fos expression was found in vlPAG and ACC (p > 0.05). CONCLUSIONS: Our study demonstrated the activation of mPFC and Sp5c in two CMMs. Olcegepant may alleviate hyperalgesia of the hind paw and periorbital area by attenuating brain activation in CMMs.

A Scoping Review of Postoperative Rehabilitation Protocols After Superior Capsular Reconstruction for Irreparable Rotator Cuff Tears.

Background: Superior capsular reconstruction (SCR) is an option for patients with massive or irreparable rotator cuff tears. Purpose: To describe the literature on rehabilitation protocols after SCR of rotator cuff tears, with emphasis on the timing of the introduction of motion. Study Design: Scoping review; Level of evidence, 4. Methods: We conducted a scoping review of articles published on PubMed, Ovid, Embase, and the Cochrane Library from inception to October 2020. The methodological index for non-randomized studies (MINORS) was used to assess the individual studies. For each article, we summarized the study characteristics, patient demographics, and rehabilitation protocols after SCR: duration of immobilization, initiation of passive range of motion (ROM), active-assisted ROM, active ROM, strengthening, and return to activities. In a subgroup narrative analysis, rehabilitation protocols were stratified by graft type: autograft versus nonautograft (xenograft, allograft, and synthetic). Results: A total of 21 studies met the search criteria. Six studies had level 3 evidence and 15 had level 4 evidence; 16 studies were considered high quality according to the MINORS score. After SCR, an abduction immobilizer was recommended for a duration of 3 to 6 weeks. Of the 21 studies, 7 (33%) started passive ROM during the first week, and 5 reported strict immobilization without motion for up to 6 weeks. All 8 studies that reported return-to-sports timing recommended delaying return until at least 6 months postoperatively. Passive ROM was recommended earlier for patients with nonautograft versus autograft (χ2 = 225; P < .001). There was a high level of heterogeneity in the rehabilitation protocols after SCR. Conclusion: The majority of published protocols were descriptive. At present, there is little agreement on the published rehabilitation guidelines after SCR, precluding specific clinical best practice suggestions. Although there was a tendency of recommending early motion in nonautograft cases, the optimal protocols based on graft healing and functional outcomes require further verification based on the clinical outcomes from high-quality studies.

Prediction of Pathogenic Factors in Dysbiotic Gut Microbiomes of Colorectal Cancer Patients Using Reverse Microbiomics.

Background: Gut microbiome plays a crucial role in the formation and progression of colorectal cancer (CRC). To better identify the underlying gene-level pathogenic mechanisms of microbiome-associated CRC, we applied our newly developed Reverse Microbiomics (RM) to predict potential pathogenic factors using the data of microbiomes in CRC patients. Results: Our literature search first identified 40 bacterial species enriched and 23 species depleted in the guts of CRC patients. These bacteria were systematically modeled and analyzed using the NCBI Taxonomy ontology. Ten species, including 6 enriched species (e.g., Bacteroides fragilis, Fusobacterium nucleatum and Streptococcus equinus) and 4 depleted species (e.g., Bacteroides uniformis and Streptococcus thermophilus) were chosen for follow-up comparative genomics analysis. Vaxign was used to comparatively analyze 47 genome sequences of these ten species. In total 18 autoantigens were predicted to contribute to CRC formation, six of which were reported with experimental evidence to be correlated with drug resistance and/or cell invasiveness of CRC. Interestingly, four human homology proteins (EDK89078.1, EDK87700.1, EDK89777.1, and EDK89145.1) are conserved among all enriched strains. Furthermore, we predicted 76 potential virulence factors without homology to human proteins, including two riboflavin synthase proteins, three ATP-binding cassettes (ABC) transporter protein family proteins, and 12 outer membrane proteins (OMPs). Riboflavin synthase is present in all the enriched strains but not in depleted species. The critical role of riboflavin synthase in CRC development was further identified from its hub role in our STRING-based protein-protein interaction (PPI) network analysis and from the finding of the riboflavin metabolism as the most significantly enriched pathway in our KEGG pathway analysis. A novel model of the CRC pathogenesis involving riboflavin synthase and other related proteins including TpiA and GrxC was further proposed. Conclusions: The RM strategy was used to predict 18 autoantigens and 76 potential virulence factors from CRC-associated microbiome data. In addition to many of these autoantigens and virulence factors experimentally verified as reported in the literature, our study predicted many new pathogenetic factors and developed a new model of CRC pathogenesis involving the riboflavin synthase from the enriched colorectal bacteria and other associated proteins.

Water quality criteria for lanthanum for freshwater aquatic organisms derived via species sensitivity distributions and interspecies correlation estimation models.

The increasing exploitation and application of rare earth elements (REEs) may induce hazardous risks to freshwater aquatic organisms. Due to the lack of water quality criteria (WQC) and sufficient reliable toxicity data, little information is available on the ecological risk of REEs in surface water. In this study, lanthanum (La) toxicity data were collected from published toxicological studies, and the data quality was assessed using a toxicological data reliability assessment tool. To obtain more toxicity data, Daphnia magna, Cyprinus carpio, and Dania rerio embryos were selected as surrogate species, and an interspecies correlation estimation (ICE) model was used to predict the toxicity of La for untested species. The species sensitivity distributions (SSDs) of La toxicity and WQC were investigated. Differences were observed in the hazardous concentrations for 5% of species (HC5), but no statistically significant differences were noted in the SSD curves between the measured acute toxicity data and the predicted data. For the SSDs constructed from the measured toxicity data, the ICE-predicted toxicity data and all acute data supplemented with the ICE-predicted data, the acute WQC values of La were 88, 1022 and 256 µg/L, respectively. According to the SSD and corresponding HC5 of chronic toxicity data, the chronic WQC was 14 µg/L. The results provide a scientific reference for establishing WQC for freshwater aquatic organisms and ecological risk assessments of REEs.

Demineralized Cortical Bone Matrix Augmented With Peripheral Blood-Derived Mesenchymal Stem Cells for Rabbit Medial Meniscal Reconstruction.

Tissue engineering is a promising treatment strategy for meniscal regeneration after meniscal injury. However, existing scaffold materials and seed cells still have many disadvantages. The objective of the present study is to explore the feasibility of peripheral blood-derived mesenchymal stem cells (PBMSCs) augmented with demineralized cortical bone matrix (DCBM) pretreated with TGF-ß3 as a tissue-engineered meniscus graft and the repair effect. PBMSCs were collected from rabbit peripheral blood and subjected to three-lineage differentiation and flow cytometry identification. DCBM was prepared by decalcification, decellularization, and cross-linking rabbit cortical bone. Various characteristics such as biomechanical properties, histological characteristics, microstructure and DNA content were characterized. The cytotoxicity and the effects of DCBM on the adhesion and migration of PBMSCs were evaluated separately. The meniscus-forming ability of PBMSCs/DCBM complex in vitro induced by TGF-ß3 was also evaluated at the molecular and genetic levels, respectively. Eventually, the present study evaluated the repair effect and cartilage protection effect of PBMSCs/DCBM as a meniscal graft in a rabbit model of medial meniscal reconstruction in 3 and 6 months. The results showed PBMSCs positively express CD29 and CD44, negatively express CD34 and CD45, and have three-lineage differentiation ability, thus can be used as tissue engineering meniscus seed cells. After the sample procedure, the cell and DNA contents of DCBM decreased, the tensile modulus did not decrease significantly, and the DCBM had a pore structure and no obvious cytotoxicity. PBMSCs could adhere and grow on the scaffold. Under induction of TGF-ß3, PBMSCs/DCBM composites expressed glycosaminoglycan (GAG), and the related gene expression also increased. The results of the in vivo experiments that the PBMSCs/DCBM group had a better repair effect than the DCBM group and the control group at both 12 and 24 weeks, and the protective effect on cartilage was also better. Therefore, the application of DCBM augmented with PBMSCs for meniscus injury treatment is a preferred option for tissue-engineered meniscus.

Derivation of water quality criteria for glyphosate and its formulations to protect aquatic life in China.

Extensive use of the herbicide glyphosate leads to a high detection rate in the environment and potential risks to nontarget aquatic life. China ranks first globally in the production and consumption of glyphosate, but there are no glyphosate water quality criteria (WQCs) for protecting aquatic life. Here, data on the acute and chronic toxicity of glyphosate and glyphosate-based formulations (GBFs) to freshwater aquatic life were collected and screened. Significant differences in species sensitivity distributions (SSDs) and toxicity values for acute or chronic toxicity were found between glyphosate and GBFs. The hazardous concentrations for 5% of species (HC5) of glyphosate or GBFs between native and nonnative species were different, and native species were found to be more sensitive to the toxicity of glyphosate. The acute and chronic WQCs derived with the SSD method for glyphosate based on the toxicity data for native species in China were 3.35 and 0.26 mg/L, respectively, and those found for GBFs were 0.21 and 0.005 mg/L, respectively. The WQCs in this study were quite different from those estimated using similar statistical extrapolation methods in other countries, which reflects the differences in species sensitivity to glyphosate toxicity in different regions. The hazard quotients (HQs) were calculated based on the WQCs and concentrations of glyphosate in some surface waters in China and indicated that glyphosate exhibits medium or high hazard risk in some samples of Tai Lake, surface water in Guiyang, fishpond water in Chongqing, rural drinking water, and surface water and reservoir water in Henan Province. The WQCs of glyphosate and GBFs have scientific significance for the exposure and pollution control of herbicide formulations and the protection of aquatic life in China.

The Effect of Intra-articular Injection of Hyaluronic Acid in Frozen Shoulder: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Frozen shoulder (FS) is a common progressive disorder that causes restricted motion and refractory pain undermining quality of life. Intra-articular hyaluronic acid (HA) injection is a widely adopted conservative therapy relieving symptomatic FS, whereas the effect of which were contradictory and unclear in current literatures. The aim of the present study is to investigate whether intra-articular HA administration facilitates symptomatic pain relief and functional improvements in patients diagnosed with shoulder FS. METHODS: The PubMed, Embase, Cochrane Library electronic databases and Google scholar were searched, from inception to 15th Jan 2022. Randomized controlled trials (RCTs) comparing intra-articular HA administration with any other non-surgical treatment in patients with FS were included. Risk of bias was evaluated using the Cochrane risk-of-bias tool and meta-analyses were undertaken to pool the data of visual analog scale for pain, range of motion (ROM) in external rotation, abduction, and flexion, as well as Shoulder Pain and Disability Index (SPADI), Constant score and American Shoulder and Elbow Surgeons (ASES). RESULTS: The present study included 7 RCTs involving 504 patients. The results provided no support for superior pain control in patients undergoing HA injection compared with any other treatment (p = 0.75). Furthermore, HA group failed to exert superior improvements to other treatments in ROM concerning abduction (p = 0.69) and flexion (p = 0.33). However, HA injection was observed to facilitate functional recovery in external rotation (p = 0.003). In addition, the pooled data showed a significant higher SPADI score in control group than in HA group (p = 0.01), while no statistical significance between two groups was observed in Constant score (p = 0.36) and ASES (p = 0.76). CONCLUSIONS: The current meta-analysis suggested that HA is a beneficial treatment procedure in improving the ROM of the shoulder for patients with FS, whereas the effect in relieving pain may be equal to the existing therapy. In conclusion, Intra-articular HA injection is recommended for FS patients.