Protective role of TRPV2 in synaptic plasticity through the ERK1/2-CREB-BDNF pathway in chronic unpredictable mild stress rats.

PURPOSE: Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms. METHODS: In vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins. RESULTS: Decreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2. CONCLUSION: These findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.

In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury.

Z-discs are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-disc-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-disc proteome in vivo. We found palmdelphin (PALMD) as a novel Z-disc-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific Palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed the transverse tubule (T-tubule)-sarcoplasmic reticulum (SR) ultrastructures, which formed the Z-disc-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with the reduction of nexilin (NEXN), a crucial Z-disc-associated protein that is essential for both Z-disc and JMC structures and functions. PALMD interacted with NEXN and enhanced its protein stability while the Nexn mRNA level was not affected. AAV-based NEXN addback rescued the exacerbated cardiac injury in isoproterenol-treated PALMD-depleted mice. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.

Magnetic Resonance Arthrogram Outperforms Standard Magnetic Resonance Imaging 2 Weeks After First Shoulder Dislocation for Labral Tear Diagnosis.

PURPOSE: To determine the comparative accuracy and precision of routine magnetic resonance imaging (MRI) versus magnetic resonance (MR) arthrogram in measuring labral tear size as a function of time from a shoulder dislocation. METHODS: We retrospectively evaluated consecutive patients who underwent primary arthroscopic stabilization between 2012 and 2021 in a single academic center. All patients completed a preoperative MRI or MR arthrogram of the shoulder within 60 days of injury and subsequently underwent arthroscopic repair within 6 months of imaging. Intraoperative labral tear size and location were used as standards for comparison. Three musculoskeletal radiologists independently interpreted tear extent using a clock-face convention. Accuracy and precision of MR labral tear measurements were defined based on location and size of the tear, respectively. Accuracy and precision were compared between MRI and MR arthrogram as a function of time from dislocation. RESULTS: In total, 32 MRIs and 65 MR arthrograms (total n = 97) were assessed. Multivariate analysis demonstrated that intraoperative tear size, early imaging, and arthrogram status were associated with increased MR accuracy and precision (P < .05). Ordering surgeons preferred arthrogram for delayed imaging (P = .018). For routine MRI, error in accuracy increased by 3.4° per day and error in precision increased by 2.3° per day (P < .001) from time of injury. MR arthrogram, however, was not temporally influenced. Significant loss of accuracy and precision of MRI compared with MR arthrogram occurred at 2 weeks after an acute shoulder dislocation. CONCLUSIONS: Compared with MR arthrogram, conventional MRI demonstrates time-dependent loss of accuracy and precision in determining shoulder labral tear extent after dislocation, with statistical divergence occurring at 2 weeks. LEVEL OF EVIDENCE: Level II, retrospective radiographic diagnostic study.

Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder.

Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K+ channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD.

Early surgery and number of injured ligaments are associated with postoperative stiffness following multi-ligament knee injury surgery: a systematic review and meta-analysis.

PURPOSE: To perform a systematic review and meta-analysis to investigate the rate of stiffness after multi-ligament knee injury (MLKI) surgery and identify potential risk factors associated with postoperative stiffness. METHODS: This study was conducted in accordance with the 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Registration was done on the PROSPERO International Prospective Register of Systematic Reviews (CRD42022321849). A literature search of PubMed, Ovid, Embase, and Cochrane Library databases was conducted in October 2022 for clinical studies reporting postoperative stiffness after MLKI surgery. A quality assessment was performed using the Methodological Index of Non-Randomized Studies (MINORS) grading system. The following variables were extracted from studies for correlation to postoperative stiffness: study characteristics, cohort demographics, Schenk classification, neurovascular injury, mechanism of injury, external fixator placement, timing of surgery, and concomitant knee injuries. RESULTS: Thirty-six studies comprising 4,159 patients who underwent MLKI surgery met the inclusion criteria, including two Level-II, fourteen Level-III, and twenty Level-IV studies. The average MINOR score of the studies was 14. The stiffness rate after MLKI was found to be 9.8% (95% CI 0.07-0.13; p < 0.01; I2 = 87%), and the risk of postoperative stiffness was significantly lower for patients with two ligaments injured compared to patients with ≥ 3 ligaments injured (OR = 0.45, 95% CI (0.26-0.79), p = 0.005; I2 = 0%). The results of the pooled analysis showed early surgery (< 3 weeks) resulted in significantly increased odds of postoperative stiffness compared with delayed surgery (≥ 3 weeks) (OR = 2.18; 95% CI 1.11-4.25; p = 0.02; I2 = 0%). However, age, gender, body mass index, energy of injury, and neurovascular injury were not associated with an increased risk of postoperative stiffness (n.s.). CONCLUSION: Performing surgery within the first 3 weeks following MLKI, or concomitant injury of ≥ 3 ligaments, are significantly associated with increased risk of postoperative stiffness. These findings can be utilized by surgeons to decide the timing of surgery for MLKI surgeries especially in which ≥ 3 ligaments are injured. LEVEL OF EVIDENCE: Level IV.

A ratiometric fluorescence sensor for tetracycline detection based on two fluorophores derived from Partridge tea.

Blue fluorescent carbon dots (PCDs) were prepared by hydrothermal method with Partridge tea. The ethanol extract of Partridge tea (PEE) was found to emit red fluorescence. Thus, a novel ratiometric sensor was constructed by simply mixing the two fluorophores derived from Partridge tea. The presence of tetracycline (TET) at lower concentrations enhanced the emission peak at 508 nm of PCDs and had a negligible effect on the emission peak at 680 nm of PEE. TET at higher concentrations led to  quenching  both the fluorescence of PCDs and PEE via inner filter effect and fluorescence resonance energy transfer, separately. Good linearities for the detection of TET were obtained in the ranges 0.67 to 15.00 µM and 33.33 to 266.67 µM, with limit of detection of 0.095 µM. The sensor was successfully applied to detect TET in lake water and milk samples with good recoveries ranging from 93.27 ± 4.04% to 107.30 ± 6.16%. This study provided a simple, selective, sensitive, rapid, and environmentally friendly method of monitoring TET residues in the environment and food.

Baclofen attenuates cognitive deficits in post-cardiac arrest brain injury.

Between 30% and 50% of survivors of cardiac arrest (CA) suffer from cognitive deficits. However, no effective medical intervention is available to alleviate cognitive deficits. Baclofen is known to protect damaged neurons, but researchers have still not clearly whether baclofen alleviates CA-induced cognitive deficits. The present study aimed to investigate whether baclofen protects against post-CA cognitive deficits and to reveal the protective mechanism of baclofen. Rats underwent 10 min of asphyxia to establish CA models. Intriguingly, our results indicated that baclofen improved spatial memory 72 h after CA. Baclofen increased plasticity-related protein (PSD95, and GAP43) expression in the brain after CA. Baclofen reduced microglial number and the release of inflammatory factors (IL-1ß and IL-18). Furthermore, baclofen significantly reduced the expression of pyroptosis-related molecules after CA. Notably, activation of NLRP3 abolished the anti-pyroptosis effect of baclofen and reduced the expression of synaptic plasticity-related proteins after CA. Taken together, this study first shows that baclofen attenuates cognitive deficits induced by brain injury after CA. The mechanism is at least partially attributed to baclofen regulating pyroptosis by inhibition of NLRP3 activation.

Evaluating the role of subacromial impingement in rotator cuff tendinopathy: development and analysis of a novel rat model.

BACKGROUND: Subacromial impingement of the rotator cuff caused by variations in acromial anatomy or altered glenohumeral kinematics leads to inflammation and degeneration of the rotator cuff, ultimately contributing to the development of tendinopathy. However, the underlying cellular and molecular changes in the impinged tendon remain poorly understood. Because the rat is an accepted model for rotator cuff studies, we have developed a rat model to study rotator cuff tendinopathy. METHODS: Forty-four adult male Sprague-Dawley rats were allocated to one of 4 study groups: intact control group (group 1, n = 11); bilateral subacromial surgical clip placement to induce supraspinatus impingement for 2 weeks (group 2, n = 11), 4 weeks (group 3, n = 11), and 8 weeks (group 4, n = 11). Bilateral shoulder specimens were harvested for biomechanical testing, histology, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RESULTS: Radiography confirmed that all microvascular clips remained in stable position in the subacromial space. Gross inspection of supraspinatus tendon specimens in the impingement groups revealed changes in tendon morphology at the enthesis and midsubstance. Biomechanical evaluation demonstrated decreased supraspinatus tendon failure force and tissue stiffness at all time points compared with control tendons. Semiquantitative scoring of histologic specimens demonstrated significant, persistent tendinopathic changes over 8 weeks. qRT-PCR analysis of impinged tendon specimens demonstrated upregulation of gene expression for Col3 and Mmp14 in the impingement groups compared with control groups. In muscle samples, significant upregulation was seen in the expression of genes that are commonly associated with muscle atrophy (MuRF1 and Ube2b) and fatty infiltration (Fabp4, Pparg2, and Klf15). CONCLUSION: This new rat subacromial impingement model creates cellular and molecular changes consistent with the development of rotator cuff tendinopathy. The results of this study may serve as a baseline for future investigation.

Current Practices for Rehabilitation After Meniscus Repair: A Survey of Members of the American Orthopaedic Society for Sports Medicine.

Background: There is no consensus among sports medicine surgeons in North America on postoperative rehabilitation strategy after meniscus repair. Various meniscal tear types may necessitate a unique range of motion (ROM) and weightbearing rehabilitation protocol. Purpose: To assess the current landscape of how sports medicine practitioners in the American Orthopedic Society for Sports Medicine (AOSSM) rehabilitate patients after the repair of varying meniscal tears. Study Design: Cross-sectional study. Methods: A survey was distributed to 2973 AOSSM members by email. Participants reviewed arthroscopic images and brief patient history from 6 deidentified cases of meniscus repair-in cases 1 to 3, the tears retained hoop integrity (more stable repair), and in cases 4 to 6, the tear patterns represented a loss of hoop integrity. Cases were shuffled before the presentation. For each case, providers were asked at what postoperative time point they would permit (1) partial weightbearing (PWB), (2) full weightbearing (FWB), (3) full ROM, and (4) ROM allowed immediately after surgery. Results: In total, 451 surveys were completed (15.2% response). The times to PWB and FWB in cases 1 to 3 (median, 0 and 4 weeks, respectively) were significantly lower than those in cases 4 to 6 (median, 4 and 6 weeks, respectively) (P < .001). In tears with retained hoop integrity, the median time to PWB was immediately after surgery, whereas in tears without hoop integrity, the median time to PWB was at 4 weeks postoperatively. Similarly, the median time to FWB in each tear with retained hoop integrity was 4 weeks after surgery, while it was 6 weeks in each tear without hoop integrity. However, regardless of tear type, most providers (67.1%) allowed 0° to 90° of ROM immediately after surgery and allowed full ROM at 6 weeks. Most providers (83.3%) braced the knee after repair regardless of hoop integrity and utilized synovial rasping/trephination with notch microfracture-a much lower proportion of providers utilized biologic augmentation (9%). Conclusion: Sports medicine practitioners in the AOSSM rehabilitated meniscal tears differently based on hoop integrity, with loss of hoop stresses triggering a more conservative approach. A majority braced and utilized in situ adjuncts for biological healing, while a minority added extrinsic biologics.

NMT2 alleviates depression-like behavior in a rat model of chronic unpredictable stress: An integrated proteomic and phosphoproteomic analysis.

Proteomics has been widely used to investigate multiple diseases. Combining the analyses of proteomics with phosphoproteomics can be used to further explain the pathological mechanisms of depression. In this study, depression-like behavior was induced in a rat model of chronic unpredictable mild stress (CUMS). We subsequently conducted the sucrose preference test, open field experiment, and forced swimming test to assess depressive-like behavior. Proteomic and phosphoproteomic sequencing of the hippocampal tissues from depressive-like behavior and normal rats were analyzed to identify differentially expressed proteins (DEPs) and differentially phosphorylated proteins (DPPs). Differentially expressed phosphorylated proteins (DEPPs) were obtained by intersecting the DEPs and DPPs, and functional enrichment analysis, as well as ingenuity pathway analysis (IPA), were subsequently performed. The study also investigated correlations among the DEPPs and used qRT-PCR to quantify the expression levels of key genes. Five DEPPs were identified, Gys1, Nmt2, Lrp1, Bin1, and Atp1a1, which were found to activate the synaptogenesis signaling pathway, induce mitochondrial dysfunction, and activate the phosphoinositide biosynthesis and degradation pathways. The qRT-PCR results confirmed the proteomic findings for Gys1, Nmt2, Lrp1, and Atp1a1. Importantly, inhibiting Nmt2 was found to alleviate depression-like behavior and alleviate neuronal apoptosis in the hippocampus of CUMS rats. In conclusion, we identified five DEPPs associated with the synaptogenesis signaling pathway, mitochondrial dysfunction, and phosphoinositide biosynthesis and degradation in depression. Furthermore, NMT2 may be a potential target for the treatment or diagnosis of depression. Our findings provide novel insights into the molecular mechanisms of depression.

Predicting Unplanned Return to Operating Room Following Primary Total Shoulder Arthroplasty: Insights from Fair and Explainable Ensemble Machine Learning.

Reoperation is the most significant complication following any surgical procedure. Developing machine learning methods that predict the need for reoperation will allow for improved shared surgical decision making and patient-specific and preoperative optimisation. Yet, no precise machine learning models have been published to perform well in predicting the need for reoperation within 30 days following primary total shoulder arthroplasty (TSA). This study aimed to build, train, and evaluate a fair (unbiased) and explainable ensemble machine learning method that predicts return to the operating room following primary TSA with an accuracy of 0.852 and AUC of 0.91.

Defining Critical Humeral Bone Loss: Inferior Craniocaudal Hill-Sachs Extension as Predictor of Recurrent Instability After Primary Arthroscopic Bankart Repair.

BACKGROUND: The glenoid track concept for shoulder instability primarily describes the medial-lateral relationship between a Hill-Sachs lesion and the glenoid. However, the Hill-Sachs position in the craniocaudal dimension has not been thoroughly studied. HYPOTHESIS: Hill-Sachs lesions with greater inferior extension are associated with increased risk of recurrent instability after primary arthroscopic Bankart repair. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The authors performed a retrospective analysis of patients with on-track Hill-Sachs lesions who underwent primary arthroscopic Bankart repair (without remplissage) between 2007 and 2019 and had a minimum 2-year follow-up. Recurrent instability was defined as recurrent dislocation or subluxation after the index procedure. The craniocaudal position of the Hill-Sachs lesion was measured against the midhumeral axis on sagittal magnetic resonance imaging (MRI) using either a Hill-Sachs bisecting line through the humeral head center (sagittal midpoint angle [SMA], a measure of Hill-Sachs craniocaudal position) or a line tangent to the inferior Hill-Sachs edge (lower-edge angle [LEA], a measure of Hill-Sachs caudal extension). Univariate and multivariate regression were used to determine the predictive value of both SMA and LEA for recurrent instability. RESULTS: In total, 176 patients were included with a mean age of 20.6 years, mean follow-up of 5.9 years, and contact sport participation of 69.3%. Of these patients, 42 (23.9%) experienced recurrent instability (30 dislocations, 12 subluxations) at a mean time of 1.7 years after surgery. Recurrent instability was found to be significantly associated with LEA >90° (ie, Hill-Sachs lesions extending below the humeral head equator), with an OR of 3.29 (P = .022). SMA predicted recurrent instability to a lesser degree (OR, 2.22; P = .052). Post hoc evaluation demonstrated that LEA >90° predicted recurrent dislocations (subset of recurrent instability) with an OR of 4.80 (P = .003). LEA and SMA were found to be collinear with Hill-Sachs interval and distance to dislocation, suggesting that greater LEA and SMA proportionally reflect lesion severity in both the craniocaudal and medial-lateral dimensions. CONCLUSION: Inferior extension of an otherwise on-track Hill-Sachs lesion is a highly predictive risk factor for recurrent instability after primary arthroscopic Bankart repair. Evaluation of Hill-Sachs extension below the humeral equator (inferior equatorial extension) on sagittal MRI is a clinically facile screening tool for higher-risk lesions with subcritical glenoid bone loss. This threshold for critical humeral bone loss may inform surgical stratification for procedures such as remplissage or other approaches for at-risk on-track lesions.

The identification of hub-methylated differentially expressed genes in osteoarthritis patients is based on epigenomic and transcriptomic data.

Introduction: Osteoarthritis (OA) refers to a commonly seen degenerative joint disorder and a major global public health burden. According to the existing literature, osteoarthritis is related to epigenetic changes, which are important for diagnosing and treating the disease early. Through early targeted treatment, costly treatments and poor prognosis caused by advanced osteoarthritis can be avoided. Methods: This study combined gene differential expression analysis and weighted gene co-expression network analysis (WGCNA) of the transcriptome with epigenome microarray data to discover the hub gene of OA. We obtained 2 microarray datasets (GSE114007, GSE73626) in Gene Expression Omnibus (GEO). The R software was utilized for identifying differentially expressed genes (DEGs) and differentially methylated genes (DMGs). By using WGCNA to analyze the relationships between modules and phenotypes, it was discovered that the blue module (MEBlue) has the strongest phenotypic connection with OA (cor = 0.92, p = 4e-16). The hub genes for OA, also known as the hub methylated differentially expressed genes, were identified by matching the MEblue module to differentially methylated differentially expressed genes. Furthermore, this study used Gene set variation analysis (GSVA) to identify specific signal pathways associated with hub genes. qRT-PCR and western blotting assays were used to confirm the expression levels of the hub genes in OA patients and healthy controls. Results: Three hub genes were discovered: HTRA1, P2RY6, and RCAN1. GSVA analysis showed that high HTRA1 expression was mainly enriched in epithelial-mesenchymal transition and apical junction; high expression of P2RY6 was mainly enriched in the peroxisome, coagulation, and epithelial-mesenchymal transition; and high expression of RCAN1 was mainly enriched in epithelial-mesenchymal-transition, TGF-ß-signaling, and glycolysis. The results of the RT-qPCR and WB assay were consistent with the findings. Discussion: The three genes tested may cause articular cartilage degeneration by inducing chondrocyte hypertrophy, regulating extracellular matrix accumulation, and improving macrophage pro-inflammatory response, resulting in the onset and progression of osteoarthritis. They can provide new ideas for targeted treatment of osteoarthritis.

Dual Versus Single Plate Fixation of Displaced Midshaft Clavicle Fractures: A Cost-Effectiveness Analysis.

BACKGROUND: Prior studies have highlighted lower rates of reoperation if fixation of a displaced midshaft clavicle fracture is performed with dual plating (DP) compared with single plating (SP). Despite higher initial costs associated with the DP construct, the observed reduction in secondary surgeries compared with the SP construct may make it a more cost-effective treatment option. The objective of this study was to assess the cost-effectiveness of DP compared with SP in patients with operatively indicated displaced midshaft clavicle fractures. METHODS: We developed a decision tree to model the occurrence of postoperative complications (acute hardware complications, wound healing issues, deep infection, nonunion, and symptomatic hardware) associated with secondary surgeries. Complication-specific risk estimates were pooled for both plating techniques using the available literature. The time horizon was 2 years, and the analysis was conducted from the health-care payer's perspective. The costs were estimated using direct medical costs, and the benefits were measured in quality-adjusted life-years (QALYs). We assumed that DP would be $300 more expensive than SP initially. We conducted probabilistic and 1-way sensitivity analyses. RESULTS: The model predicted reoperation in 6% of patients in the DP arm compared with 14% of patients in the SP arm. In the base case analysis, DP increased QALYs by 0.005 and costs by $71 per patient, yielding an incremental cost-effectiveness ratio (ICER) of $13,242 per QALY gained. The sensitivity analysis demonstrated that the cost-effectiveness of DP was driven by the cost of the index surgery, risk of symptomatic hardware, and nonunion complications with SP and DP. At a willingness-to-pay threshold of $100,000 per QALY gained, 95% of simulations suggested that DP was cost-effective compared with SP. CONCLUSIONS: When indicated, operative management of displaced midshaft clavicle fractures using DP was found to be cost-effective compared with SP. Despite its higher initial hardware costs, DP fixation appears to offset its added costs with greater health utility via lower rates of reoperation and improved patient quality of life. LEVEL OF EVIDENCE: Economic and Decision Analysis Level II . See Instructions for Authors for a complete description of levels of evidence.

GABAB Receptor Activation Attenuates Neuronal Pyroptosis in Post-cardiac Arrest Brain Injury.

Brain injury is a major cause of death and disability after cardiac arrest (CA). Previous studies have shown that activating GABAB receptors significantly improves neurological function after CA, but the mechanism of this neuronal protection of damaged neurons remains unclear. Thus, the present study aimed to investigate whether GABAB receptor activation protects against neuronal injury and to reveal the underlying protective mechanisms. In this study, rats underwent 10 min of asphyxia to induce CA, and SH-SY5Y cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish in vivo and in vitro models of hypoxic neuronal injury. Differential gene expression between CA rats and sham-operated rats was identified using RNA-seq. TUNEL and Nissl staining were used to evaluate cortical neuron damage, while Western blotting, qRT-PCR, and immunofluorescence assays were conducted to measure pyroptosis-related indicators. Furthermore, cellular models with high expression of caspase-11 were established to reveal the novel molecular mechanisms by which GABAB receptor activation exerts neuroprotective effects. Intriguingly, our results showed that caspase-11 and GSDMD were highly expressed in rats experiencing cardiac arrest. Specifically, GSDMD was expressed in neurons in the M1 area of the cerebral cortex. Moreover, activation of the GABAB receptor exerted a protective effect on neurons both in vivo and in vitro. Baclofen attenuated caspase-11 activation and neuronal pyroptosis after CA, and the anti-neuronal pyroptosis effect of baclofen was abolished by overexpression of caspase-11 in neuronal cells. In conclusion, GABAB receptor activation may play a neuroprotective role by alleviating neuronal pyroptosis through a mechanism involving caspase-11.

Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice.

Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.

The Role of Indian Hedgehog Signaling in Tendon Response to Subacromial Impingement: Evaluation Using a Mouse Model.

BACKGROUND: The underlying cellular and molecular mechanisms involved in the development of tendinopathy due to subacromial supraspinatus tendon (SST) impingement and the response to subsequent removal of impingement remain unknown. PURPOSE: To investigate the involvement of Indian hedgehog (IHH) signaling in the development of SST tendinopathy and the subsequent healing process after the relief of subacromial impingement in a novel mouse shoulder impingement model. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 48 male wild-type C57BL/6 mice were used in this study. Supraspinatus tendinopathy was induced by inserting a microsurgical clip into the subacromial space bilaterally. Eleven mice were sacrificed at 4 weeks after surgery to establish impingement baseline; 24 mice underwent clip removal at 4 weeks after surgery and then were euthanized at 2 or 4 weeks after clip removal. Thirteen mice without surgical intervention were utilized as the control group. All SSTs were evaluated with biomechanical testing; quantitative histomorphometry after staining with hematoxylin and eosin, Alcian blue, and picrosirius red; and immunohistochemical staining (factor VIII, IHH, Patched1 [PTCH1], and glioma-associated oncogene homolog 1 [GLI1]). RESULTS: The mean failure force and stiffness in the 4-week impingement group decreased significantly compared with the control group (P < .001) and gradually increased at 2 and 4 weeks after clip removal. Histological analysis demonstrated increased cellularity and disorganized collagen fibers in the SST, with higher modified Bonar scores at 4 weeks, followed by gradual improvement after clip removal. The IHH-positive area and PTCH1- and GLI1-positive cell percentages significantly increased after 4 weeks of clip impingement (20.64% vs 2.06%, P < .001; 53.9% vs 28.03%, P = .016; and 30% vs 12.19%, P = .036, respectively) and continuously increased after clip removal. CONCLUSION: The authors' findings suggest that the hedgehog signaling pathway and its downstream signaling mediator and target GLI1 may play a role in the development and healing process of rotator cuff tendinopathy due to extrinsic rotator cuff impingement. CLINICAL RELEVANCE: This study suggests the potential for the hedgehog pathway, together with its downstream targets, as candidates for further study as potential therapeutic targets in the treatment of supraspinatus tendinopathy.

Assessing Hemorrhagic Shock Severity Using the Second Heart Sound Determined from Phonocardiogram: A Novel Approach.

Introduction: Hemorrhagic shock (HS) is a severe medical emergency. Early diagnosis of HS is important for clinical treatment. In this paper, we report a flexible material-based heart sound monitoring device which can evaluate the degree of HS through a phonocardiogram (PCG) change. Methods: Progressive hemorrhage treatments (H1, H2, and H3 stage) were used in swine to build animal models. The PCG sensor was mounted on the chest of the swine. Routine monitoring was used at the same time. Results: This study showed that arterial blood pressure decreased significantly from the H1 phase, while second heart sound amplitude (S2A) and energy (S2E) decreased significantly from the H2 phase. Both S2A and S2E correlated well with BP (p < 0.001). The heart rate, pulse pressure variation and serum hemoglobin level significantly changed in the H3 stage (p < 0.05). Discussion: The change of second heart sound (S2) was at the H2 stage and was earlier than routine monitoring methods. Therefore, PCG change may be a new indicator for the early detection of HS severity.

Identification of Potential Diagnoses Based on Immune Infiltration and Autophagy Characteristics in Major Depressive Disorder.

Background: Major depressive disorder (MDD) is a serious mental illness characterized by mood changes and high suicide rates. However, no studies are available to support a blood test method for MDD diagnosis. The objective of this research was to identify potential peripheral blood biomarkers for MDD and characterize the novel pathophysiology. Methods: We accessed whole blood microarray sequencing data for MDD and control samples from public databases. Biological functions were analysed by GO and KEGG pathway enrichment analyses using the clusterprofile R package. Infiltrated immune cell (IIC) proportions were identified using the CIBERSORT algorithm. Clustering was performed using the ConsensusClusterPlus R package. Protein-protein interactions (PPI) were assessed by constructing a PPI network using STRING and visualized using Cytoscape software. Rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks to induce stress behaviour. Stress behaviour was evaluated by open field experiments and forced swimming tests. Flow cytometry was used to analyse the proportion of CD8+ T cells. The expression of the corresponding key genes was detected by qRT-PCR. Results: We divided MDD patients into CD8H and CD8L clusters. The functional enrichment of marker genes in the CD8H cluster indicated that autophagy-related terms and pathways were significantly enriched. Furthermore, we obtained 110 autophagy-related marker genes (ARMGs) in the CD8H cluster through intersection analysis. GO and KEGG analyses further showed that these ARMGs may regulate a variety of autophagy processes and be involved in the onset and advancement of MDD. Finally, 10 key ARMGs were identified through PPI analysis: RAB1A, GNAI3, VAMP7, RAB33B, MYC, LAMP2, RAB11A, HIF1A, KIF5B, and PTEN. In the CUMS model, flow cytometric analysis confirmed the above findings. qRT-PCR revealed significant decreases in the mRNA levels of Gnai3, Rab33b, Lamp2, and Kif5b in the CUMS groups. Conclusion: In this study, MDD was divided into two subtypes. We combined immune infiltrating CD8+ T cells with autophagy-related genes and screened a total of 10 ARMG genes. In particular, RAB1A, GNAI3, RAB33B, LAMP2, and KIF5B were first reported in MDD. These genes may offer new hope for the clinical diagnosis of MDD.

Conceptualizing Biological Aging and Frailty in Orthopaedics: A Framework for Clinical Practice.

➤: Biological aging can best be conceptualized clinically as a combination of 3 components: frailty, comorbidity, and disability. ➤: Despite advancements in the understanding of senescence, chronological age remains the best estimate of biological age. However, a useful exercise for practitioners is to look beyond chronological age in clinical and surgical decision-making. ➤: A chronologically aging person does not age biologically at the same rate. ➤: The best way to understand frailty is to consider it as a physical phenotype. ➤: Physical optimization should parallel medical optimization before elective surgery. ➤: The poorer the host (both in terms of bone quality and propensity for healing), the more robust the implant construct must be to minimize reliance on host biology.