Cell membrane coated nanoparticles: cutting-edge drug delivery systems for osteoporosis therapy.

Osteoporosis, characterized by a reduction in bone mineral density, represents a prevalent skeletal disorder with substantial global health implications. Conventional therapeutic strategies, exemplified by bisphosphonates and hormone replacement regimens, though effective, encounter inherent limitations and challenges. Recent years have witnessed the surge of cell-membrane-coated nanoparticles (CMNPs) as a promising intervention for osteoporosis, leveraging their distinct attributes including refined biocompatibility, heightened pharmaceutical payload capacity, as well as targeted drug release kinetics. However, a comprehensive review consolidating the application of CMNPs-based therapy for osteoporosis remains absent within the existing literature. In this review, we provide a concise overview of the distinctive pathogenesis associated with osteoporosis, alongside an in-depth exploration of the physicochemical attributes intrinsic to CMNPs derived from varied cellular sources. Subsequently, we explore the potential utility of CMNPs, elucidating emerging trends in their deployment for osteoporosis treatment through multifaceted therapeutic approaches. By linking the notable attributes of CMNPs with their roles in mitigating osteoporosis, this review serves as a catalyst for further advances in the design of advanced CMNPs tailored for osteoporosis management. Ultimately, such progress is promising for enhancing outcomes in anti-bone loss interventions, paving the way for clinical translation in the near future.

Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates.

Protein ubiquitylation controls diverse processes within eukaryotic cells, including protein degradation, and is often dysregulated in disease. Moreover, small-molecule degraders that redirect ubiquitylation activities toward disease targets are an emerging and promising therapeutic class. Over 600 E3 ubiquitin ligases are expressed in humans, but their substrates remain largely elusive, necessitating the development of new methods for their discovery. Here we report the development of E3-substrate tagging by ubiquitin biotinylation (E-STUB), a ubiquitin-specific proximity labeling method that biotinylates ubiquitylated substrates in proximity to an E3 ligase of interest. E-STUB accurately identifies the direct ubiquitylated targets of protein degraders, including collateral targets and ubiquitylation events that do not lead to substrate degradation. It also detects known substrates of E3 ligase CRBN and VHL with high specificity. With the ability to elucidate proximal ubiquitylation events, E-STUB may facilitate the development of proximity-inducing therapeutics and act as a generalizable method for E3-substrate mapping.

Association of consumption of sugar-sweetened beverages with elevated blood pressure among college students in Yunnan Province, China.

OBJECTIVE: Although some studies have examined the association between eating behaviour and elevated blood pressure (EBP) in adolescents, current data on the association between sugar-sweetened beverages (SSB) and EBP in adolescents in Yunnan Province, China, are lacking. SETTING: Cluster sampling was used to survey freshmen at a college in Kunming, Yunnan Province, from November to December. Data on SSB consumption were collected using an FFQ measuring height, weight and blood pressure. A logistic regression model was used to analyse the association between SSB consumption and EBP, encompassing prehypertension and hypertension with sex-specific analyses. PARTICIPANTS: The analysis included 4781 college students. RESULTS: Elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) were detected in 35·10 % (1678/4781) and 39·34 % (1881/4781) of patients, respectively. After adjusting for confounding variables, tea beverage consumption was associated with elevated SBP (OR = 1·24, 95 % CI: 1·03, 1·49, P = 0·024), and carbonated beverage (OR = 1·23, 95 % CI: 1·04, 1·45, P = 0·019) and milk beverage (OR = 0·81, 95 % CI: 0·69, 0·95, P = 0·010) consumption was associated with elevated DBP in college students. Moreover, fruit beverage (OR = 1·32, 95 % CI: 1·00, 1·75, P = 0·048) and milk beverage consumption (OR = 0·69, 95 % CI: 0·52, 0·93, P = 0·014) was associated with elevated DBP in males. CONCLUSION: Our findings indicated that fruit and milk beverage consumption was associated with elevated DBP in males, and no association was observed with EBP in females.

HDAC6/aggresome processing pathway importance for inflammasome formation is context-dependent.

The inflammasome is a large multiprotein complex that assembles in the cell cytoplasm in response to stress or pathogenic infection. Its primary function is to defend the cell and promote the secretion of pro-inflammatory cytokines, including IL-1ß and IL-18. Previous research has shown that in immortalized bone marrow-derived macrophages (iBMDMs) inflammasome assembly is dependent on the deacetylase HDAC6 and the aggresome processing pathway (APP), a cellular pathway involved in the disposal of misfolded proteins. Here we used primary BMDMs from mice in which HDAC6 is ablated or impaired and found that inflammasome activation was largely normal. We also used human peripheral blood mononuclear cells and monocyte cell lines expressing a synthetic protein blocking the HDAC6-ubiquitin interaction and impairing the APP and found that inflammasome activation was moderately affected. Finally, we used a novel HDAC6 degrader and showed that inflammasome activation was partially impaired in human macrophage cell lines with depleted HDAC6. Our results therefore show that HDAC6 importance in inflammasome activation is context-dependent.

Copper incorporated biomaterial-based technologies for multifunctional wound repair.

The treatment of wounds is a worldwide challenge, and wound infection can affect the effectiveness of wound treatment and further increase the disease burden. Copper is an essential trace element that has been shown to have broad-spectrum antibacterial effects and to be involved in the inflammation, proliferation, and remodeling stages of wound healing. Compared to treatments such as bioactive factors and skin grafts, copper has the advantage of being low-cost and easily available, and has received a lot of attention in wound healing. Recently, biomaterials made by incorporating copper into bioactive glasses, polymeric scaffolds and hydrogels have been used to promote wound healing by the release of copper ions. In addition, copper-incorporated biomaterials with catalytic, photothermal, and photosensitive properties can also accelerate wound healing through antibacterial and wound microenvironment regulation. This review summarizes the antibacterial mechanisms of copper- incorporated biomaterials and their roles in wound healing, and discusses the current challenges. A comprehensive understanding of the role of copper in wounds will help to facilitate new preclinical and clinical studies, thus leading to the development of novel therapeutic tools.

Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss.

The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3'-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.

Neddylation suppression by a macrophage membrane-coated nanoparticle promotes dual immunomodulatory repair of diabetic wounds.

Oxidative stress, infection, and vasculopathy caused by hyperglycemia are the main barriers for the rapid repair of foot ulcers in patients with diabetes mellitus (DM). In recent times, the discovery of neddylation, a new type of post-translational modification, has been found to regulate various crucial biological processes including cell metabolism and the cell cycle. Nevertheless, its capacity to control the healing of wounds in diabetic patients remains unknown. This study shows that MLN49224, a compound that inhibits neddylation at low concentrations, enhances the healing of diabetic wounds by inhibiting the polarization of M1 macrophages and reducing the secretion of inflammatory factors. Moreover, it concurrently stimulates the growth, movement, and formation of blood vessel endothelial cells, leading to expedited healing of wounds in individuals with diabetes. The drug is loaded into biomimetic macrophage-membrane-coated PLGA nanoparticles (M-NPs/MLN4924). The membrane of macrophages shields nanoparticles from being eliminated in the reticuloendothelial system and counteracts the proinflammatory cytokines to alleviate inflammation in the surrounding area. The extended discharge of MLN4924 from M-NPs/MLN4924 stimulates the growth of endothelial cells and the formation of tubes, along with the polarization of macrophages towards the anti-inflammatory M2 phenotype. By loading M-NPs/MLN4924 into a hydrogel, the final formulation is able to meaningfully repair a diabetic wound, suggesting that M-NPs/MLN4924 is a promising engineered nanoplatform for tissue engineering.

Macrophage-mediated fracture healing: Unraveling molecular mechanisms and therapeutic implications using hydrogel-based interventions.

Fracture healing is a complex biological process that involves the orchestrated interplay of various cells and molecular signaling pathways. Among the key players, macrophages have emerged as critical regulators of fracture repair, influencing inflammation, tissue remodeling, and angiogenesis. Recent advances in hydrogel-based therapeutics have provided exciting opportunities to leverage the modulatory effects of macrophages for improving fracture healing outcomes. In the present study, we review the importance of macrophages in fracture repair and their potential therapeutic role in hydrogel-based interventions. We discuss the molecular mechanisms underlying macrophage-mediated effects on fracture healing, and how hydrogels can be utilized as a platform for macrophage modulation. Furthermore, we highlight the translation of hydrogel-based therapies from bench to bedside, including preclinical and clinical studies, and the challenges and opportunities in harnessing the therapeutic potential of macrophages in fracture repair. Overall, understanding the importance of macrophages in fracture healing and the potential of hydrogel-based therapeutics to modulate macrophage responses can pave the way for developing innovative approaches to improve fracture healing outcomes.

Adjuvant Therapy-Free Strategy for Stage IB to IIIA Non-Small-Cell Lung Cancer Patients After Radical Resection Based on Longitudinal Undetectable Molecular Residual Disease: Prospective, Multicenter, Single-Arm Study (CTONG 2201).

BACKGROUND: The utility of circulating tumor DNA to monitor molecular residual disease (MRD) has been clinically confirmed to predict disease recurrence in non-small cell lung cancer (NSCLC) patients after radical resection. Patients with longitudinal undetectable MRD show a favorable prognosis and might not benefit from adjuvant therapy. PATIENTS AND METHODS: The CTONG 2201 trial is a prospective, multicenter, single-arm study (ClinicalTrials.gov identifier, NCT05457049), designed to evaluate the hypothesis that no adjuvant therapy is needed for patients with longitudinal undetectable MRD. Pathologically confirmed stage IB-IIIA NSCLC patients who have undergone radical resection will be screened. Only patients with 2 consecutive rounds of undetectable MRD will be enrolled (first at days 3-10, second at days 30 ± 7 after surgery), and admitted for imaging and MRD monitoring every 3 months without adjuvant therapy. The primary endpoint is the 2-year disease-free survival rate for those with longitudinal undetectable MRD. The recruitment phase began in August 2022 and 180 patients will be enrolled. CONCLUSIONS: This prospective trial will contribute data to confirm the negative predictive value of MRD on adjuvant therapy for NSCLC patients. CLINICAL TRIAL REGISTRATION: NCT05457049 (CTONG 2201).

Metal-Organic Frameworks and Their Composites for Chronic Wound Healing: From Bench to Bedside.

Chronic wounds are characterized by delayed and dysregulated healing processes. As such, they have emerged as an increasingly significant threat. The associated morbidity and socioeconomic toll are clinically and financially challenging, necessitating novel approaches in the management of chronic wounds. Metal-organic frameworks (MOFs) are an innovative type of porous coordination polymers, with low toxicity and high eco-friendliness. Documented anti-bacterial effects and pro-angiogenic activity predestine these nanomaterials as promising systems for the treatment of chronic wounds. In this context, the therapeutic applicability and efficacy of MOFs remain to be elucidated. It is, therefore, reviewed the structural-functional properties of MOFs and their composite materials and discusses how their multifunctionality and customizability can be leveraged as a clinical therapy for chronic wounds.

Volume-Confined Fabrication of Large-Scale Single-Crystalline Molecular Ferroelectric Thin Films and Their Applications in 2D Materials.

With outstanding advantages of chemical synthesis, structural diversity, and mechanical flexibility, molecular ferroelectrics have attracted increasing attention, demonstrating themselves as promising candidates for next-generation wearable electronics and flexible devices in the film form. However, it remains a challenge to grow high-quality thin films of molecular ferroelectrics. To address the above issue, a volume-confined method is utilized to achieve ultrasmooth single-crystal molecular ferroelectric thin films at the sub-centimeter scale, with the thickness controlled in the range of 100-1000 nm. More importantly, the preparation method is applicable to most molecular ferroelectrics and has no dependency on substrates, showing excellent reproducibility and universality. To demonstrate the application potential, two-dimensional (2D) transitional metal dichalcogenide semiconductor/molecular ferroelectric heterostructures are prepared and investigated by optical spectroscopic method, proving the possibility of integrating molecular ferroelectrics with 2D layered materials. These results may unlock the potential for preparing and developing high-performance devices based on molecular ferroelectric thin films.

CYP1A inhibitors: Recent progress, current challenges, and future perspectives.

Mammalian cytochrome P450 1A (CYP1A) are key phase I xenobiotic-metabolizing enzymes that play a distinctive role in metabolic activation or metabolic clearance of a variety of procarcinogens, drugs, and endogenous substances. Human CYP1A subfamily contains two members (hCYP1A1 and hCYP1A2), which are known to catalyze the oxidative activation of some environmental procarcinogens into carcinogenic species. Increasing evidence has demonstrated that CYP1A inhibitor therapies are promising strategies for cancer chemoprevention or overcoming CYP1A-associated drug toxicity and resistance. Herein, we reviewed recent advances in the discovery and characterization of hCYP1A inhibitors, from the discovery approaches to structural features and biomedical applications of hCYP1A inhibitors. The inhibition potentials, inhibition modes, and inhibition constants of all reported hCYP1A inhibitors are comprehensively summarized. Meanwhile, the structural features and structure-activity relationships of different classes of hCYP1A1 and hCYP1A2 inhibitors are analyzed and discussed in depth. Furthermore, the major challenges and future directions for this field are presented and highlighted. Collectively, the information and knowledge presented here will strongly facilitate the researchers to discover and develop more efficacious CYP1A inhibitors for specific purposes, such as chemo-preventive agents or as tool molecules in hCYP1A-related fundamental studies.

First Observation of Negative Capacitance in Molecular Ferroelectric Thin Films.

On the path of persisting Moore's Law, one of the biggest obstacles is the "Boltzmann tyranny," which defines the lower limit of power consumption of individual transistors. Negative capacitance (NC) in ferroelectrics could provide a solution and has garnered significant attention in the fields of nanoelectronics, materials science, and solid-state physics. Molecular ferroelectrics, as an integral part of ferroelectrics, have developed rapidly in terms of both performance and functionality, with their inherent advantages such as easy fabrication, mechanical flexibility, low processing temperature, and structural tunability. However, studies on the NC in molecular ferroelectrics are limited. In this study, the focus is centered on the fabricated high-quality thin films of trimethylchloromethyl ammonium trichlorocadmium(II), and a pioneering investigation on their NC responses is conducted. The findings demonstrate that the NC exhibited by molecular ferroelectrics is comparable to that of conventional HfO2 -based ferroelectrics. This underscores the potential of molecular material systems for next-generation electronic devices.

An instant messaging mobile phone application for promoting HIV pre-exposure prophylaxis uptake among Chinese gay, bisexual and other men who have sex with men: A mixed methods feasibility and piloting randomized controlled trial study.

BACKGROUND: Mobile health (mHealth) is a promising intervention mode for HIV prevention, but little is known about its feasibility and effects in promoting pre-exposure prophylaxis (PrEP) uptake among Chinese gay, bisexual and other men who have sex with men (GBMSM). METHODS: We evaluated an instant messaging application using a WeChat-based mini-app to promote PrEP uptake among GBMSM via a mixed-methods design that includes a 12-week, two-arm randomized controlled pilot trial and in-depth progress interviews in Guangzhou, China. Primary outcomes include the number of PrEP initiations, individual-level psychosocial variables related to PrEP initiation, and usability of the PrEP mini-app. RESULTS: Between November 2020 and April 2021, 70 GBMSM were successfully enrolled and randomized into two arms at 2:1 ratio (46 to the intervention arm, 24 to the control arm). By the end of 12-week follow-up, 22 (31.4%) participants completed the initial consultation and lab tests for PrEP, and 13 (18.6%) filled their initial PrEP prescription. We observed modest but non-significant improvements in participants' intention to use PrEP, actual PrEP initiation, PrEP-related self-efficacy, stigma, and attitudes over 12 weeks when comparing the mini-app and the control arms. Qualitative interviews revealed the key barriers to PrEP uptake include anticipated stigma and discrimination in clinical settings, burden of PrEP care, and limited operating hours of the PrEP clinic. In-person clinic navigation support was highly valued. CONCLUSIONS: This pilot trial of a mobile phone-based PrEP mini-app demonstrated feasibility and identified limitations in facilitating PrEP uptake among Chinese GBMSM. Future improvements may include diversifying the content presentation in engaging media formats, adding user engagement features, and providing off-line in-clinic navigation support during initial PrEP visit. More efforts are needed to understand optimal strategies to identify and implement alternative PrEP provision models especially in highly stigmatized settings with diverse needs. TRIAL REGISTRATION: Trial registration: The study was prospectively registered on clinicaltrials.gov (NCT04426656) on 11 June, 2020.

Identification of Key Influencers for Secondary Distribution of HIV Self-Testing Kits Among Chinese Men Who Have Sex With Men: Development of an Ensemble Machine Learning Approach.

BACKGROUND: HIV self-testing (HIVST) has been rapidly scaled up and additional strategies further expand testing uptake. Secondary distribution involves people (defined as "indexes") applying for multiple kits and subsequently sharing them with people (defined as "alters") in their social networks. However, identifying key influencers is difficult. OBJECTIVE: This study aimed to develop an innovative ensemble machine learning approach to identify key influencers among Chinese men who have sex with men (MSM) for secondary distribution of HIVST kits. METHODS: We defined three types of key influencers: (1) key distributors who can distribute more kits, (2) key promoters who can contribute to finding first-time testing alters, and (3) key detectors who can help to find positive alters. Four machine learning models (logistic regression, support vector machine, decision tree, and random forest) were trained to identify key influencers. An ensemble learning algorithm was adopted to combine these 4 models. For comparison with our machine learning models, self-evaluated leadership scales were used as the human identification approach. Four metrics for performance evaluation, including accuracy, precision, recall, and F1-score, were used to evaluate the machine learning models and the human identification approach. Simulation experiments were carried out to validate our approach. RESULTS: We included 309 indexes (our sample size) who were eligible and applied for multiple test kits; they distributed these kits to 269 alters. We compared the performance of the machine learning classification and ensemble learning models with that of the human identification approach based on leadership self-evaluated scales in terms of the 2 nearest cutoffs. Our approach outperformed human identification (based on the cutoff of the self-reported scales), exceeding by an average accuracy of 11.0%, could distribute 18.2% (95% CI 9.9%-26.5%) more kits, and find 13.6% (95% CI 1.9%-25.3%) more first-time testing alters and 12.0% (95% CI -14.7% to 38.7%) more positive-testing alters. Our approach could also increase the simulated intervention's efficiency by 17.7% (95% CI -3.5% to 38.8%) compared to that of human identification. CONCLUSIONS: We built machine learning models to identify key influencers among Chinese MSM who were more likely to engage in secondary distribution of HIVST kits. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) ChiCTR1900025433; https://www.chictr.org.cn/showproj.html?proj=42001.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Waste to Wealth: Near-Infrared/pH Dual-Responsive Copper-Humic Acid Hydrogel Films for Bacteria-Infected Cutaneous Wound Healing.

The clinical applications of currently used photosensitizers are limited by high costs, inconvenient preparation, suboptimal biodegradability, and a lack of biological activity. Humic acids (HAs) show photothermal activity and can be used as a photosensitizer for photothermal therapy. In the presence of various functional groups, HAs are endowed with anti-inflammatory and antioxidant activities. The solubility of HAs is dependent on the pH value, which is soluble in neutral to alkaline conditions and undergoes a conformational change to a coiled and compact structure in acidic conditions. Additionally, Cu2+ is an emerging therapeutic agent for cutaneous wounds and can be chelated by HAs to form complexes. In this study, we explore the ability of HAs to modulate the inflammatory response, particularly macrophage polarization, and the potential underlying mechanism. We fabricate a near-infrared (NIR)/pH dual-responsive Cu-HAs nanoparticle (NP)-based poly(vinyl alcohol) (PVA) hydrogel film loaded with SEW2871 (SEW), a macrophage recruitment agent, to treat bacteria-infected cutaneous wounds. The results show that HAs could promote M2 macrophage polarization in a dose-dependent manner. The Cu-HAs NPs successfully eradicated bacterial infection through NIR-induced local hyperthermia. This PVA@Cu-HAs NPs@SEW hydrogel film improves tissue regeneration by promoting M2 macrophage polarization, alleviating oxidative stress, enhancing angiogenesis, and facilitating collagen deposition. These findings highlight the therapeutic potential of PVA@Cu-HAs NPs@SEW hydrogel film for the treatment of bacterially infected cutaneous wound healing.

HDAC6/aggresome processing pathway importance for inflammasome formation is context dependent.

The inflammasome is a large multiprotein complex that assembles in the cell cytoplasm in response to stress or pathogenic infection. Its primary function is to defend the cell and promote the secretion of pro-inflammatory cytokines, including IL-1ß and IL-18. It was shown that in immortalized bone marrow derived macrophages (iBMDMs) inflammasome assembly is dependent on the deacetylase HDAC6 and the aggresome processing pathway (APP), a cellular pathway involved in the disposal of misfolded proteins. Here we used primary BMDMs from mice in which HDAC6 is ablated or impaired and found that inflammasome activation was largely normal. We also used human peripheral blood mononuclear cells and monocytes cell lines expressing a synthetic protein blocking HDAC6-ubiquitin interaction and impairing the APP and found that inflammasome activation was moderately affected. Finally, we used a novel HDAC6 degrader and showed that inflammasome activation was partially impaired in human macrophage cell lines with depleted HDAC6. Our results therefore show that HDAC6 importance in inflammasome activation is context dependent.

The 2022 Massive Open Online Course (MOOC) to train physiotherapists in the management of people with spinal cord injuries: a qualitative and quantitative analysis of learners' experiences and its impact.

STUDY DESIGN: Observational. OBJECTIVES: To determine the learners' experience and the impact of a Massive Open Online Course (MOOC) conducted to teach physiotherapists about the management of people with spinal cord injuries (SCI). METHODS: A SCI MOOC for physiotherapists was run in 5 different languages at the end of 2022. Qualitative and quantitative data were collected from different sources including registration details, pre- and post-MOOC Knowledge Assessments, a post-MOOC Evaluation, social media posts and online tracking of websites and emails. The data were used to answer four key questions: (i) what was the reach of the MOOC, (ii) what did participants think about the MOOC (iii) did the MOOC change participants' knowledge and/or confidence, and (iv) did the MOOC change participants' clinical practice or the way they teach others? RESULTS: 25,737 people from 169 countries registered for the MOOC. 98% of participants who completed the Evaluation (n = 2281) rated the MOOC as either "good" or "very good". Participants' knowledge improved by a median (IQR) of 25% (10 to 45%) (n = 4016 participants) on the MOOC Knowledge Assessment. Participants reported changes in confidence, and intentions to change clinical practice and incorporate what they had learnt into the way they teach others in response to the MOOC. CONCLUSION: The MOOC provided an efficient way to increase physiotherapists' knowledge about the physiotherapy management of people with SCI. Participants enjoyed the MOOC, and indicated an intention to change clinical practice and the way they taught others.