Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

Research progress and hotspots on macrophages in osteoarthritis: A bibliometric analysis from 2009 to 2022.

BACKGROUND: Macrophages in the synovium, as immune cells, can be polarized into different phenotypes to play an anti-inflammatory role in the treatment of osteoarthritis. In this study, bibliometric methods were used to search the relevant literature to find valuable research directions for researchers and provide new targets for osteoarthritis prevention and early treatment. METHODS: Studies about the application of macrophages in the treatment of osteoarthritis were searched through the Web of Science core database from 2009 to 2022. Microsoft Excel 2019, VOSviewer, CiteSpace, R software, and 2 online websites were used to analyze the research status and predict the future development of the trend in research on macrophages in osteoarthritis. RESULTS: The number of publications identified with the search strategy was 1304. China and the United States ranked first in the number of publications. Shanghai Jiao Tong University ranked first in the world with 37 papers. Osteoarthritis and Cartilage was the journal with the most publications, and "exosomes," "stem cells," "macrophage polarization," "regeneration," and "innate immunity" may remain the research hotspots and frontiers in the future. CONCLUSION: The findings from the global trend analysis indicate that research on macrophages in the treatment of osteoarthritis is gradually deepening, and the number of studies is increasing. Exosomes may become a research trend and hotspot in the future.

Preclinical Studies and Clinical Trials on Cell-Based Treatments for Meniscus Regeneration.

This study aims at performing a thorough review of cell-based treatment strategies for meniscus regeneration in preclinical and clinical studies. The PubMed, Embase, and Web of Science databases were searched for relevant studies (both preclinical and clinical) published from the time of database construction to December 2022. Data related to cell-based therapies for in situ regeneration of the meniscus were extracted independently by two researchers. Assessment of risk of bias was performed according to the Cochrane Handbook for Systematic Reviews of Interventions. Statistical analyses based on the classification of different treatment strategies were performed. A total of 5730 articles were retrieved, of which 72 preclinical studies and 6 clinical studies were included in this review. Mesenchymal stem cells (MSCs), especially bone marrow MSCs (BMSCs), were the most commonly used cell type. Among preclinical studies, rabbit was the most commonly used animal species, partial meniscectomy was the most commonly adopted injury pattern, and 12 weeks was the most frequently chosen final time point for assessing repair outcomes. A range of natural and synthetic materials were used to aid cell delivery as scaffolds, hydrogels, or other morphologies. In clinical trials, there was large variation in the dose of cells, ranging from 16 × 106 to 150 × 106 cells with an average of 41.52 × 106 cells. The selection of treatment strategy for meniscus repair should be based on the nature of the injury. Cell-based therapies incorporating various "combination" strategies such as co-culture, composite materials, and extra stimulation may offer greater promise than single strategies for effective meniscal tissue regeneration, restoring natural meniscal anisotropy, and eventually achieving clinical translation. Impact Statement This review provides an up-to-date and comprehensive overview of preclinical and clinical studies that tested cell-based treatments for meniscus regeneration. It presents novel perspectives on studies published in the past 30 years, giving consideration to the cell sources and dose selection, delivery methods, extra stimulation, animal models and injury patterns, timing of outcome assessment, and histological and biomechanical outcomes, as well as a summary of findings for individual studies. These unique insights will help to shape future research on the repair of meniscus lesions and inform the clinical translation of new cell-based tissue engineering strategies.

MicroRNA expression in osteoarthritis: a meta-analysis.

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases globally, leading to chronic disability and poor prognosis. One of the approaches for optimizing OA treatment is to find early effective diagnostic biomarkers. The contribution of microRNAs (miRNAs) in OA progression is now being increasingly recognized. This review provides a comprehensive summary on studies reporting the expression profiling of miRNAs in OA and associated signaling pathways. We performed a systematic search of the Embase, Web of Science, PubMed, and Cochrane library databases. This systematic review is reported according to the PRISMA checklist. Studies which identified miRNAs with aberrant expression compared to controls during OA progression were included, and a meta-analysis was performed. Results from the random effects model were provided as log10 odds ratios (logORs) and 95% confidence intervals. Sensitivity analysis was conducted to confirm the accuracy of the results. Subgroup analysis was conducted based on tissue source. The target genes of miRNAs identified in this study were extracted from the MiRWalk database, and these target genes were enriched in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. A total of 191 studies reporting 162 miRNAs were included in our meta-analysis. Among them, 36 miRNAs distributed across 96 studies were expressed in the same direction in at least two studies (13 up-regulated and 23 down-regulated). Subgroup analysis of tissue source revealed that the highest number of studies was conducted using articular cartilage, where the most up-regulated miRNAs were miR-146a-5p (logOR 7.355; P < 0.001) and miR-34a-5p (logOR 6.955; P < 0.001), and the most down-regulated miRNAs were miR-127-5p (logOR 6.586; P < 0.001) and miR-140-5p (logOR 6.373; P < 0.001). Enrichment analysis of 752 downstream target genes of all identified miRNAs was performed, and the regulatory relationships among them were displayed. Mesenchymal stem cells and transforming growth factor-ß were found to be the most important downstream effectors regulated by miRNA in OA. This study highlighted the importance of miRNA signaling in OA progression and identified a number of prominent miRNAs including miR-146a-5p, miR-34a-5p, miR-127-5p, and miR-140-5p which might be considered as potential biomarkers for OA.

Biomaterials for Tissue-Engineered Treatment of Tendinopathy in Animal Models: A Systematic Review.

To conduct a systematic review of studies reporting the treatment of tendon injury using biomaterials in animal models. A systematic search was conducted to retrieve studies involving animal models of tendon repair using biomaterials, in PubMed (database construction to August 2022) and Ovid-Embase (1946 to August 2022). Data related to tendon repair with biomaterials were extracted by two researchers, respectively. Risk of bias was assessed following the Cochrane Handbook for Systematic Reviews of Interventions. A statistical analysis was performed based on the classification of tendon repair biomaterials included in our study. A total of 8413 articles were retrieved, with 78 studies included in our analysis. For tendon repair in animal models using biomaterials, the most commonly seen characteristics were as follows: naturally derived biomaterials, rabbits and rats as animal models, surgery as the injury model, and the Achilles tendon as the injury site. The histology and biomechanical recovery of tendon injury following repair are affected by different biomaterials. Studies of tendon repair in animal models indicate that biomaterials can significantly improve repair outcomes, including tendon structure and biomechanics. Among effective biomaterial strategies are the use of new composites and incorporation of cells or growth factors into the material, both of which provide obvious benefits for tendon healing. More high-quality preclinical studies are required to encourage the translation of biomaterials into clinical practice for tendon repair.

Failure modes after anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

PURPOSE: The reason for graft failure after anterior cruciate ligament reconstruction (ACLR) is multifactorial. Controversies remain regarding the predominant factor and incidence of failure aetiology in the literature. This review aimed to provide a meta-analysis of the literature to evaluate the relative proportion of various failure modes among patients with ACLR failure. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, and EBSCO databases were searched for literature on ACLR failure or revision from 1975 to 2021. Data related to causes for ACLR surgical failure were extracted, and a random effects model was used to pool the results, which incorporates potential heterogeneity. Failure modes were compared between different populations, research methods, graft types, femoral portal techniques, and fixation methods by subgroup analysis or linear regression. Funnel plots were used to identify publication bias and small-study effects. RESULTS: A total of 39 studies were analyzed, including 33 cohort studies and six registry-based studies reporting 6578 failures. The results showed that among patients with ACLR failure or revision, traumatic reinjury was the most common failure mode with a rate of 40% (95% CI: 35-44%), followed by technical error (34%, 95% CI: 28-42%) and biological failure (11%, 95% CI: 7-15%). Femoral tunnel malposition was the most common cause of the technical error (29%, 95% CI: 18-41%), with more than two times higher occurrence than tibial tunnel malposition (11%, 95% CI: 6-16%). Traumatic reinjury was the most common factor for ACLR failure in European populations and in recent studies, while technical errors were more common in Asian populations, earlier studies, and surgery performed using the transtibial (TT) portal technique. Biological factors were more likely to result in ACLR failure in hamstring (HT) autografts compared to bone-patellar tendon-bone (BPTB) autografts. CONCLUSION: Trauma is the most important factor leading to surgical failure or revision following ACLR. Technical error is also an important contributing factor, with femoral tunnel malposition being the leading cause of error resulting in failure.

A mechanics model in design of flexible nozzle with multiple movable hinge boundaries.

In this paper, we propose a modified variational approach to predict the morphology of the flexible nozzle used in wind tunnel. Different from previous studies, the movements of the multiple hinges are considered as movable displacement boundary conditions during establishing the potential energy functional. The cubic spline interpolation method is employed to supply the supplementary boundary conditions in calculation of the functional minimization problem. Current analytical model is verified by experiments carried out on a fixed-flexible nozzle structure whose geometries and materials are the same as those from a commissioned supersonic nozzle. The maximum deviation between the predictions from theoretical method and laser displacement testing does not exceed 0.5 mm. This method can also deal with the large deflection beam problem with multiple movable boundaries.

A Highly Accurate Method for Deformation Reconstruction of Smart Deformable Structures Based on Flexible Strain Sensors.

Smart deformable structures that integrate designing, sensing, and controlling technology have been widely applied in the fields of aerospace, robotics, and biomedical engineering due to their multi-functional requirements. The deformation reconstruction method essential for security monitoring and shape controlling, especially for the large deflection deformation, remains a challenge on accuracy and efficiency. This paper takes a wind tunnel's fixed-flexible nozzle (FFN) plate as the research object to develop a highly accurate deformation reconstruction method based on sensing information from flexible strain sensors. The mechanical behaviors of the FFN plate with large deflection deformation, which is modeled as a cantilever beam, are studied to analyze the relationship of the strain and moment. Furthermore, the large deflection factor and shell bending theory are creatively utilized to derive and modify the strain-moment based reconstruction method (SMRM), where the contour of the FFN plate is solved by particular elliptic integrals. As a result, structural simulation based on ABAQUS further demonstrates that the reconstruction error of SMRM is 21.13% less than that of the classic Ko-based reconstruction method (KORM). An FFN prototype accompanied by customized flexible sensors is developed to evaluate the accuracy and efficiency of the SMRM, resulting in a maximum relative error of 3.97% that is acceptable for practical applications in smart deformable structures, not limited to the FFN plate.

Enrichment of residual carbon from coal gasification fine slag by spiral separator.

Coal gasification is one of the most promising clean coal technologies. However, gasification process also produces a huge amount of solid waste of high carbon content, named coal gasification fine slag. The coal gasification fine slag is mainly handled by landfilling, which is not only a hazardous pollution, but also wasting the energy from residual carbon. Developing a technology to utilize coal gasification fine slag and recover the residual carbon is becoming essential for an eco-friendly coal chemical industry. In this paper, the enrichment behavior of residual carbon in coal gasification fine slag by a spiral separator is studied. The raw coal gasification fine slag sample and separator products are characterized on particle size distribution, size-depending ash content, reactivity, micromorphology and porous structure. The experimental results show that the spiral separator is efficient to remove ash and enriched carbonaceous components in coal gasification fine slag by separating feed (100%) into concentrate (81.2%), middlings (8.8%), and tailings (10.08%), where the ash content in tailings is up to 90%, accounting for 18.5% of total ash in feeding. The beneficial product "concentrate" has a good distribution of size-depending ash content, that most combustibles are enriched in these particles of diameter >100 µm. After spiral separator, the concentrate products have a more pure and developed porous structure with the surface area increasing from 199.8 m2/g (feeding) to 231.8 m2/g, as well as a better combustion reactivity of lower ignition temperature compared with feedings. Accordingly, an economic and feasible combination process of spiral separator connecting sieve can produce an enriched-carbon product of ∼45% yield and ∼80% carbonaceous content. The Iodine adsorption ability of sieved products increases by 47.6% compared with feed, and reaches up to about half of industry activated carbon. The finally sieved concentrate products have a good market prospect as fuel and adsorbent.

Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses.

AIM: To provide a systematic analysis of the study design in knee osteoarthritis (OA) preclinical studies, focusing on the characteristics of animal models and cell doses, and to compare these to the characteristics of clinical trials using mesenchymal stem cells (MSCs) for the treatment of knee OA. METHOD: A systematic and comprehensive search was conducted using the PubMed, Web of Science, Ovid, and Embase electronic databases for research papers published in 2009-2020 on testing MSC treatment in OA animal models. The PubMed database and ClinicalTrials.gov website were used to search for published studies reporting clinical trials of MSC therapy for knee OA. RESULTS: In total, 9234 articles and two additional records were retrieved, of which 120 studies comprising preclinical and clinical studies were included for analysis. Among the preclinical studies, rats were the most commonly used species for modeling knee OA, and anterior cruciate ligament transection was the most commonly used method for inducing OA. There was a correlation between the cell dose and body weight of the animal. In clinical trials, there was large variation in the dose of MSCs used to treat knee OA, ranging from 1 × 106 to 200 × 106 cells with an average of 37.91 × 106 cells. CONCLUSION: Mesenchymal stem cells have shown great potential in improving pain relief and tissue protection in both preclinical and clinical studies of knee OA. Further high-quality preclinical and clinical studies are needed to explore the dose effectiveness relationship of MSC therapy and to translate the findings from preclinical studies to humans.

Cost Effectiveness of Pharmacological Management for Osteoarthritis: A Systematic Review.

BACKGROUND AND OBJECTIVE: Osteoarthritis (OA) is a highly prevalent, disabling disease requiring chronic management that is associated with an enormous individual and societal burden. This systematic review provides a global cost-effectiveness evaluation of pharmacological therapy for the management of OA. METHODS: Following Center for Reviews and Dissemination (CRD) guidance, a literature search strategy was undertaken using PubMed, EMBASE, Cochrane Library, Health Technology Assessment (HTA) database, and National Health Service Economic Evaluation database (NHS EED) to identify original articles containing cost-effectiveness evaluation of OA pharmacological treatment published before 4 November 2021. Risk of bias was assessed by two independent reviewers using the Joanna Briggs Institute (JBI) critical appraisal checklist for economic evaluations. The Quality of Health Economic Studies (QHES) instrument was used to assess the reporting quality of included articles. RESULTS: Database searches identified 43 cost-effectiveness analysis studies (CEAs) on pharmacological management of OA that were conducted in 18 countries and four continents, with one study containing multiple continents. A total of four classes of drugs were assessed, including non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), and intra-articular (IA) injections. The methodological approaches of these studies showed substantial heterogeneity. The incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) were (in 2021 US dollars) US$44.40 to US$307,013.56 for NSAIDS, US$11,984.84 to US$128,028.74 for opioids, US$10,930.17 to US$27,799.73 for SYSADOAs, and US$258.36 to US$58,447.97 for IA injections in different continents. The key drivers of cost effectiveness included medical resources, productivity, relative risks, and selected comparators. CONCLUSION: This review showed substantial heterogeneity among studies, ranging from a finding of dominance to very high ICERs, but most studies found interventions to be cost effective based on specific ICER thresholds. Important challenges in the analysis were related to the standardization and methodological quality of studies, as well as the presentation of results.

Animal Models for Treating Spinal Cord Injury Using Biomaterials-Based Tissue Engineering Strategies.

The aim of the study is to provide an up-to-date review of studies that used preclinical animal models for the evaluation of tissue engineering treatments for spinal cord injury (SCI), which involved the use of biomaterials with or without the addition of cells or biomolecules. Electronic search of the PubMed, Web of Science, and Embase databases was performed for relevant studies published between January 2009 and December 2019. In total, 1579 articles were retrieved, of which 58 studies were included for analysis. Among the included studies, rats were the most common species used for animal models of SCI, while complete transection was the most commonly used injury pattern. Immediate intervention after injury was conducted in the majority of studies, and 8 weeks was the most common final time point of outcome assessment. A wide range of natural and synthetic biomaterials with different morphologies were used as a part of tissue engineering treatments for SCI, including scaffolds, hydrogels, and particles. Experimental parameters in studies using SCI animal models to evaluate tissue engineering treatments should be carefully considered to match the purpose of the study. Biomaterials that have functional modifications or are applied in combination with cells and biomolecules can be effective in creating a permissive environment for SCI repair in preclinical animal models. Impact statement This review provides an up-to-date summary of the preclinical landscape where tissue engineering treatments involving biomaterials were tested in animal models of spinal cord injury (SCI). Using studies published within the last 10 years, novel perspectives were presented on the animal species used, injury pattern, timing of intervention and outcome measurement, and biomaterials selection, as well as a summary of the individual findings of each study. This review provides unique insight into biomaterials-based tissue engineering strategies that have progressed to testing in animal models of SCI, which will help shape future research in the field and propel the clinical translation of discoveries.

Large-Size Suspended Mono-Layer Graphene Film Transfer Based on the Inverted Floating Method.

Suspended graphene can perfectly present the excellent material properties of graphene, which has a good application prospect in graphene sensors. The existing suspended graphene pressure sensor has several problems that need to be solved, one of which is the fabrication of a suspended sample. It is still very difficult to obtain large-size suspended graphene films with a high integrity that are defect-free. Based on the simulation and analysis of the kinetic process of the traditional suspended graphene release process, a novel setup for large-size suspended graphene release was designed based on the inverted floating method (IFM). The success rate of the single-layer suspended graphene with a diameter of 200 µm transferred on a stainless-steel substrate was close to 50%, which is greatly improved compared with the traditional impregnation method. The effects of the defects and burrs around the substrate cavity on the stress concentration of graphene transfer explain why the transfer success rate of large-size suspended graphene is not high. This research lays the foundation for providing large-size suspended graphene films in the area of graphene high-precision sensors.

A novel combination of graphene and silver nanowires for entirely stretchable and ultrasensitive strain sensors: sandwich-based sensing films.

A great deal of engineering effort is focused on developing stretchable strain sensors for human motion monitoring and wearable devices. The ultrasensitivity and fast response under tiny strain (1%) while maintaining the working range remain the grand challenge. In this work, we propose an entirely stretchable strain sensor based on the sandwich sensing film, which is fabricated by vacuum filtration of silver nanowires (AgNWs)/ graphene/ AgNWs in sequence and the injection of liquid metal as electrodes. The novel sandwich sensing film endows the stretchable strain sensor high sensitivity under tiny strain (Gauge factor = 111.5 at 1%), fast response (<10 ms), relative large working range (0%-35%) with a maximum gauge factor of 1403.7, followed by good linearity, long-term durability, and the recovery property from being overstretched (>100%). The excellent performance is due to the slippage of the inner graphene under tiny strain, whereas the 'sewing' phenomenon of the outer AgNWs under larger strain. The sandwich structure illustrates a better combination of graphene and AgNWs than other hybrid methods, showing great potential in wearable devices and soft robotics.