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Abstract Severe tissue defects present formidable challenges to human health, persisting as major contributors to mortality rates. The complex pathological microenvironment, particularly the disrupted immune landscape within these defects, poses substantial hurdles to existing tissue regeneration strategies. However, the emergence of nanobiotechnology has opened a new direction in immunomodulatory nanomedicine, providing encouraging prospects for tissue regeneration and restoration. This review aims to gather recent advances in immunomodulatory nanomedicine to foster tissue regeneration. We begin by elucidating the distinctive features of the local immune microenvironment within defective tissues and its crucial role in tissue regeneration. Subsequently, we explore the design and functional properties of immunomodulatory nanosystems. Finally, we address the challenges and prospects of clinical translation in nanomedicine development, aiming to propose a potent approach to enhance tissue regeneration through synergistic immune modulation and nanomedicine integration.

Abstract Ageing as a natural irreversible process inherently results in the functional deterioration of numerous organ systems and tissues, including the skeletal and immune systems. Recent studies have elucidated the intricate bidirectional interactions between these two systems. In this review, we provide a comprehensive synthesis of molecular mechanisms of cell ageing. We further discuss how age-related skeletal changes influence the immune system and the consequent impact of immune system alterations on the skeletal system. Finally, we highlight the clinical implications of these findings and propose potential strategies to promote healthy ageing and reduce pathologic deterioration of both the skeletal and immune systems.

Abstract Infected fracture healing is a complicated process that includes intricate interactions at the cellular and molecular levels. In addition to angiogenesis and osteogenesis, the significance of neurogenesis in fracture healing has also been recognized in recent years. Here, a nanocomposite hydrogel containing pH‐responsive zinc‐gallium‐humic acids (HAs) nanoparticles is developed. Through the timed release of Zn2+, Ga3+, and HAs, the hydrogel exhibits potent antibacterial effects and promotes angiogenesis, osteogenesis, and neurogenesis. The enhanced neurogenesis further promotes angiogenesis and osteogenesis, forming a mutually supportive angiogenesis–osteogenesis–neurogenesis cycle at the fracture site. The hydrogel achieves rapid infected fracture healing and improves tissue regeneration in mice. This study proposes a comprehensive treatment approach that combines antibacterial effects with the regulation of tissue regeneration to improve infected fracture healing.

BackgroundOver the past 23 years, there has been a thorough analysis of literature concerning nutritional interventions, nutrients, and feeding approaches related to stroke. Furthermore, a scientific knowledge map was established, elucidating the current state of research, examining its development and trends, and offering new research viewpoints for the future. This study aimed to investigate global and emerging research trends in nutritional interventions for stroke from 2000 to 2023 through bibliometric analysis.MethodsA bibliometric analysis of literature from the Core Collection of Scientific Networks for the years 2000–2022 was conducted. CiteSpace, VOSviewer, and bibliometric graphical software were used to identify major contributors to publications, including authors, countries, institutions, journals, references, and keywords.ResultsThe bibliometric analysis yielded a total of 464 publications. This is a gradually increasing number in terms of the number of publications during the study period. China had the highest number of publications. Clinical Nutrition” was the journal with the highest number of relevant publications, and the most commonly used keywords were “stroke,” “nutrition” and “malnutrition.”ConclusionThese analyses reveal research trends in nutritional therapy for stroke from 2000 to 2023 and point to prospective research frontiers. This study provides a deeper understanding of what nutritional treatment of stroke entails and provides guidance and support for future research in this area.

Abstract Mangrove forests are critical coastal ecosystems that provide great socio‐ecological services, which are also highly vulnerable to climate change, particularly to sea level rise (SLR). Here we assess changes in mangrove forests in four distinct river/tide/wave‐dominant large deltas along the Indo‐Pacific coast based on 1,336 remote sensing images by machine learning techniques. We find that mangroves are migrating seaward at a rate of 18% ± 12% m/yr, which can offset landward mangroves loss, 67% of which caused by land use conversion. The fact that mangroves are expanding seaward with accretion rates exceeding SLR suggests that climate change has not yet triggered substantial loss in deltaic mangrove forests. Assuming that present environmental conditions do not change and that sediment and organic deposition in the deltaic topsets match SLR rates, we project that 90% of deltaic mangrove forests may start to retreat after 132–194 years. Early inundation of mangroves will occur in wave‐dominated delta.

Gene therapy has emerged as a highly promising strategy for the clinical treatment of large segmental bone defects and non-union fractures, which is a common clinical need. Meanwhile, many preclinical data have demonstrated that gene and cell therapies combined with optimal scaffold biomaterials could be used to solve these tough issues. Bone tissue engineering, an interdisciplinary field combining cells, biomaterials, and molecules with stimulatory capability, provides promising alternatives to enhance bone regeneration. To deliver and localize growth factors and associated intracellular signaling components into the defect site, gene therapy strategies combined with bioengineering could achieve a uniform distribution and sustained release to ensure mesenchymal stem cell osteogenesis. In this review, we will describe the process and cell molecular changes during normal fracture healing, followed by the advantages and disadvantages of various gene therapy vectors combined with bone tissue engineering. The growth factors and other bioactive peptides in bone regeneration will be particularly discussed. Finally, gene-activated biomaterials for bone regeneration will be illustrated through a description of characteristics and synthetic methods.

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.

It is imperative to develop and implement newer, more effective strategies to address refractory diabetic wounds. As of now, there is currently no optimal solution for these wounds. Hypoxic human umbilical vein endothelial cells (HUVECs)-derived exosomes have been postulated to promote diabetic wound healing, however, its effect and molecular mechanism need further study. In this study, we aimed to investigate whether hypoxic exosomes enhance wound healing in diabetics. Based on our high-throughput sequencing, differentially expressed lncRNAs (including 64 upregulated lncRNAs and 94 downregulated lncRNAs) were found in hypoxic exosomes compared to normoxic exosomes. Interestingly, lncHAR1B was one of the prominently upregulated lncRNAs in hypoxic exosomes, showing a notable correlation with diabetic wound healing. More specifically, hypoxic exosomes were transmitted to surrounding cells, which resulted in a significant increase in lncHAR1B level, thereby relieving the dysfunction of endothelial cells and promoting the switch from M1 to M2 macrophages under high glucose conditions. Mechanistically, lncHAR1B directly interacted with the transcription factor basic helix-loop-helix family member e23 (BHLHE23), which subsequently led to its binding to the KLF transcription factor 4 (KLF4) and promoted KLF4 expression. In our in vivo experiments, the use of hypoxic exosomes-loaded HGM-QCS hydrogels (Gel-H-Exos) resulted in rapid wound healing compared to that of normoxic exosomes-loaded HGM-QCS hydrogels (Gel-N-Exos) and diabetic groups. Consequently, our study provides potentially novel therapeutic approaches aimed at accelerating wound healing and developing a practical exosomes delivery platform.

Osteoarthritis (OA) represents an enduring and widespread global burden, causing significant morbidity and disability, whose pathology is characterized by persistent inflammation, progressive cartilage degeneration, abnormal bone homeostasis, and excessive synovial hyperplasia, resulting from its complex microenvironment. Unfortunately, current therapeutic approaches for OA remain suboptimal, prompting increased interest in advanced nanotechnology as a means to enhance therapeutic effects. In recent years, significant progress has been made in the development of versatile nanoplatforms designed to the specific microenvironment of OA, resulting in promising results and introducing the concept of “OA nanomedicine”. Compared to the conventional therapies like non-steroidal anti-inflammatory drugs (NSAIDs), OA nanomedicine offers precise targeted, controllable and personalized ways for OA therapy, contributing to better outcomes. However, a comprehensive review consolidating the “OA nanomedicine” is currently absent from literature. Therefore, in this review, we aim to unravel the key pathological and microenvironmental characteristics of OA while summarizing the properties and advantages of nanosystems possessing microenvironment-reprogramming capabilities for OA therapy. First, we make a retrospection of the features of OA pathology and OA microenvironment. Furthermore, we provide an overview of the advances in OA nanomedicine. Eventually, we discuss the present challenges associated with OA nanomedicine and provide insights into its future prospects from a clinical-translational lens. By doing so, this review can foster and propel the successful development of OA nanomedicine, addressing the unmet needs in OA therapy.

Abstract 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.

The diabetic wounds remain to be unsettled clinically, with chronic wounds characterized by drug-resistant bacterial infections, compromised angiogenesis and oxidative damage to the microenvironment. To ameliorate oxidative stress and applying antioxidant treatment in the wound site, we explore the function of folliculin-interacting protein 1 (FNIP1), a mitochondrial gatekeeper protein works to alter mitochondrial morphology, reduce oxidative phosphorylation and protect cells from unwarranted ROS accumulation. And our in vitro experiments showed the effects of FNIP1 in ameliorating oxidative stress and rescued impaired angiogenesis of HUVECs in high glucose environment. To realize the drug delivery and local regulation of FNIP1 in diabetic wound sites, a novel designed glucose-responsive HA-PBA-FA/EN106 hydrogel is introduced for improving diabetic wound healing. Due to the dynamic phenylboronate ester structure with a phenylboronic acid group between hyaluronic acid (HA) and phenylboronic acid (PBA), the hydrogel is able to realize a glucose-responsive release of drugs. Fulvic acid (FA) is added in the hydrogel, which not only severs as crosslinking agent but also provides antibacterial and anti-inflammatory abilities. Moreover, the release of FEM1b-FNIP1 axis inhibitor EN106 ameliorated oxidative stress and stimulated angiogenesis through FEM1b-FNIP1 axis regulation. These in vivo and in vitro results demonstrated that accelerated diabetic wounds repair with the use of the HA-PBA-FA/EN106 hydrogel, which may provide a promising strategy for chronic diabetic wound repair.

Objectives To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent.Methods In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18.Results 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): –1.03 (–1.66 to –0.40) vs –0.58 (–1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement.Conclusions Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA.Trial registration number NCT04991753.

Abstract The association between rosacea and inflammatory bowel disease (IBD) has been studied in previous observational studies. It is unclear, however, whether the association is causal or not. Independent genetic variants for IBD were chosen as instruments from published Genome-wide association studies (GWAS) studies involving 38,155 cases with an IBD diagnosis and 48,485 controls in order to investigate the causal effect of IBD on rosacea. Summarized data for rosacea were gathered from various GWAS studies that included 1195 cases and 211,139 controls without rosacea. Reverse-direction Mendelian randomization (MR) analysis was done to investigate the relationship between genetically proxied rosacea and IBD. With the use of the inverse variance-weighted (IVW), MR-Egger, and weighted median approaches, a 2-sample Mendelian randomization study was carried out. Analysis of heterogeneity and sensitivity was performed to examine the pleiotropy and robustness of effect estimates. The forward-direction of the MR study was to reveal that genetic predisposition to IBD including its two main subtypes: Crohn’s disease (CD) and ulcerative colitis (UC) was associated with an increased risk of rosacea. The reverse-direction MR analyses did not demonstrate that a genetic predisposition to rosacea was associated with total IBD, UC and CD. Our findings provided evidence for a causal impact of IBD, UC, and CD on rosacea, but not vice versa. The elevated incidence of rosacea in patients with IBD should be recognized by doctors to make an early diagnosis and initiate specialized therapy.

Abstract Various joint pathologies such as osteochondritis dissecans, osteonecrosis, rheumatic disease, and trauma, may result in severe damage of articular cartilage and other joint structures, ranging from focal defects to osteoarthritis (OA). The osteochondral unit is one of the critical actors in this pathophysiological process. New approaches and applications in tissue engineering and regenerative medicine continue to drive the development of OA treatment. Hydrogel scaffolds, a component of tissue engineering, play an indispensable role in osteochondral regeneration. In this review, tissue engineering strategies regarding osteochondral regeneration were highlighted and summarized. The application of hydrogels for osteochondral regeneration within the last five years was evaluated with an emphasis on functionalized physical and chemical properties of hydrogel scaffolds, functionalized delivery hydrogel scaffolds as well as functionalized intelligent response hydrogel scaffolds. Lastly, to serve as guidance for future efforts in the creation of bioinspired hydrogel scaffolds, a succinct summary and new views for specific mechanisms, applications, and existing limitations of the newly designed functionalized hydrogel scaffolds were offered. Graphical Abstract

Fracture nonunion remains a great challenge for orthopedic surgeons. Fracture repair comprises of three phases, the inflammatory, repair and remodeling stage. Extensive advancements have been made in the field of bone repair, including development of strategies to balance the M1/M2 macrophage populations, and to improve osteogenesis and angiogenesis. However, such developments focused on only one or the latter two phases, while ignoring the inflammatory phase during which cell recruitment occurs. In this study, we combined Stromal Cell-Derived Factor-1α (SDF-1α) and M2 macrophage derived exosomes (M2D-Exos) with a hyaluronic acid (HA)-based hydrogel precursor solution to synthesize an injectable, self-healing, adhesive HA@SDF-1α/M2D-Exos hydrogel. The HA hydrogel demonstrated good biocompatibility and hemostatic ability, with the 4% HA hydrogels displaying great antibacterial activity against gram-negative E. coli and gram-positive S. aureus and Methicillin-resistant Staphylococcus aureus (MRSA). Synchronously and sustainably released SDF-1α and M2D-Exos from the HA@SDF-1α/M2D-Exos hydrogel enhanced proliferation and migration of human bone marrow mesenchymal stem cell (HMSCs) and Human Umbilical Vein Endothelial Cells (HUVECs), promoting osteogenesis and angiogenesis both in vivo and in vitro. Overall, the developed HA@ SDF-1α/M2D-Exos hydrogel was compatible with the natural healing process of fractures and provides a new modality for accelerating bone repair by coupling osteogenesis, angiogenesis, and resisting infection at all stages.

ObjectiveOur aim was to determine the number and size parameters of EDB motor units in healthy young adults using MScanFit, a novel approach to motor unit number estimation (MUNE). Since variability in MUNE is related to compound muscle action potential (CMAP) size, we employed a procedure to document the optimal EDB electromyographic (EMG) electrode position prior to recording MUNE, a neglected practice in MUNE.MethodsSubjects were 21 adults 21-44 y. Maximum CMAPs were recorded from 9 sites in a 4 cm2 region centered over the EDB and the site with the largest amplitude was used in the MUNE experiment. For MUNE, the peroneal nerve was stimulated at the fibular head to produce a detailed EDB stimulus-response curve or "MScan". Motor unit number and size parameters underlying the MScan were simulated using the MScanFit mathematical model.ResultsIn 19 persons, the optimal recording site was superior, superior and proximal, or superior and distal to the EDB mid-belly, whereas in 3 persons it was proximal to the mid-belly. Ranges of key MScanFit parameters were as follows: maximum CMAP amplitude (3.1-8.5 mV), mean SMUP amplitude (34.4-106.7 μV), mean normalized SMUP amplitude (%CMAP max, 0.95-2.3%), largest SMUP amplitude (82.7-348 μV), and MUNE (43-103). MUNE was not related to maximum CMAP amplitude (R2 = 0.09), but was related to mean SMUP amplitude (R2 = -0.19, P = 0.05).ConclusionThe EDB CMAP was highly sensitive to electrode position, and the optimal position differed between subjects. Individual differences in EDB MUNE were not related to CMAP amplitude. Inter-subject variability of EDB MUNE (coefficient of variation) was much less than previously reported, possibly explained by better optimization of the EMG electrode and the unique approach of MScanFit MUNE.

Abstract 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.

Bone fracture: faster healing after traumatic brain injury Extracellular vesicles enriched with a particular microRNA released following traumatic brain injury (TBI) help fractures heal faster and could inform treatments for skeletal disorders. Patients with TBI and associated fractures experience shorter fracture recovery times than patients with fractures only, but precisely why is unclear. Ze Lin at Huazhong University of Science and Technology, Wuhan, China, and co-workers examined molecules released during recovery in samples taken from patients with TBI and fractures, those with fractures only, and mouse models with femur fractures. They found that exosomes (extracellular vesicles that transport metabolites including microRNA) released following TBI are enriched with miRNA-21-5 p, which enhances differentiation of bone-forming cells and bone repair. No miRNA-21-5 p enrichment occurred in patients with fractures only. Knocking out exosomal miRNA-21-5 p impaired bone repair in mice, while injecting exosomes from TBI patients boosted bone formation.

Abstract Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering (TE) and regenerative medicine. In contrast to conventional biomaterials or synthetic materials, biomimetic scaffolds based on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo extracellular matrix (ECM). Additionally, such materials have mechanical adaptability, microstructure interconnectivity, and inherent bioactivity, making them ideal for the design of living implants for specific applications in TE and regenerative medicine. This paper provides an overview for recent progress of biomimetic natural biomaterials (BNBMs), including advances in their preparation, functionality, potential applications and future challenges. We highlight recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs with various biological and physicochemical characteristics of native ECM. Moreover, we offer an overview of recent key advances in the functionalization and applications of versatile BNBMs for TE applications. Finally, we conclude by offering our perspective on open challenges and future developments in this rapidly-evolving field.

The Schlieren technique is widely adopted for visualizing supersonic jets owing to its non-invasiveness to the flow field. However, extending the classical Schlieren method for quantitative refractive index measurements is cumbersome, especially for three-dimensional supersonic flows. Background-oriented Schlieren has gained increasing popularity owing to its ease of implementation and calibration. This study utilizes multi-view-based tomographic background-oriented Schlieren (TBOS) to reconstruct axisymmetric and weakly non-axisymmetric supersonic jets, highlighting the impact of flow axisymmetry breaking on TBOS reconstructions. Several classical TBOS reconstruction algorithms, including FDK, SART, SIRT, and CGLS, are compared quantitatively regarding reconstruction quality. View spareness is identified to be the main cause of degraded reconstruction quality when the flow experiences axisymmetry breaking. The classic visual hull approach is explored to improve reconstruction quality. Together with the CGLS tomographic algorithm, we successfully reconstruct the weakly non-axisymmetric supersonic jet structures and confirm that increasing the nozzle bevel angle leads to wider jet spreads.

BackgroundHIV 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. ObjectiveThis 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. MethodsWe 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. ResultsWe 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. ConclusionsWe built machine learning models to identify key influencers among Chinese MSM who were more likely to engage in secondary distribution of HIVST kits. Trial RegistrationChinese Clinical Trial Registry (ChiCTR) ChiCTR1900025433; https://www.chictr.org.cn/showproj.html?proj=42001

Abstract A growing body of evidence suggests that patients who experience traumatic brain injuries (TBIs) exhibit significantly shorter healing periods compared to those with isolated fractures. However, the precise underlying mechanism behind this phenomenon remains unclear. Recent studies have shed light on the potential role of hormonal signals and neural circuits originating in the hypothalamus, which play vital roles in regulating the skeletal system. Despite these advances, there is a lack of comprehensive research summarizing the crucial role of bone healing in TBIs and the underlying mechanisms. This review aimed to explore the underlying mechanisms responsible for the accelerated bone healing observed in TBI patients, with a specific focus on the intricate crosstalk between TBI and bone remodeling. Additionally, we comprehensively discuss and summarize the beneficial effects of TBI on the skeletal system and examine the TBI‐induced signaling pathways that result in accelerated fracture healing and bone remodeling. By dissecting these pathways, we aim to identify potential targets for intervention and bone repair promotion.

Abstract Skeletal tissue is highly innervated. Although different types of nerves have been recently identified in the bone, the crosstalk between bone and nerves remains unclear. In this review, we outline the role of the peripheral nervous system (PNS) in bone regeneration following injury. We first introduce the conserved role of nerves in tissue regeneration in species ranging from amphibians to mammals. We then present the distribution of the PNS in the skeletal system under physiological conditions, fractures, or regeneration. Furthermore, we summarize the ways in which the PNS communicates with bone-lineage cells, the vasculature, and immune cells in the bone microenvironment. Based on this comprehensive and timely review, we conclude that the PNS regulates bone regeneration through neuropeptides or neurotransmitters and cells in the peripheral nerves. An in-depth understanding of the roles of peripheral nerves in bone regeneration will inform the development of new strategies based on bone-nerve crosstalk in promoting bone repair and regeneration.

Major traumatic tissue defects are common clinical problems often complicated by infection and local vascular dysfunction, processes which hinder the healing process. Although local application of growth factors or stem cells through various tissue engineering techniques are promising methods for the repair of tissue defects, limitations in their clinical application exist. Herein, we synthesized multifaceted nanohybrids composed of Quaternized chitosan (QCS), Graphene oxide (GO), and Polydopamine (PDA; QCS-GO-PDA). Covalent grafting of QCS and GO at a mass ratio of 5:1 (5QCS-1GO) displayed excellent biocompatibility and enhanced osteogenic ability, while addition of PDA (5QCS-1GO-PDA) reduced the level of reactive oxygen species (ROS). 5QCS-1GO-PDA was able to achieve wound tissue regeneration by reducing the inflammatory response and enhancing angiogenesis. Furthermore, Polylactic acid/hydroxyapatite (PLA/HA) composite scaffolds were printed using Selective Laser Sintering (SLS) and the hybrid nanomaterial (5QCS-1GO-PDA) was used to coat the PLA/HA scaffold (5QCS-1GO-PDA@PLA/HA) to be used for rapid bone regeneration. 5QCS-1GO-PDA not only improved angiogenesis and osteogenic differentiation, but also induced M2-type polarization of macrophages and promoted bone regeneration via the BMP2/BMPRs/Smads/Runx2 signaling pathway. The bidirectional enhanced healing ability of the multifaceted nanohybrids 5QCS-1GO-PDA provides a promising method of effectively treating tissue defects.

Abstract Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.

Abstract Background Adherent pre-exposure prophylaxis (PrEP) uptake can prevent HIV infections. Despite the high HIV incidence, Chinese key populations have low PrEP uptake and adherence. New interventions are needed to increase PrEP adherence among key populations in China. Co-creation methods are helpful to solicit ideas from the community to solve public health problems. The study protocol aims to describe the design of a stepped-wedge trial and to evaluate the efficacy of co-created interventions to facilitate PrEP adherence among key populations in China. Methods The study will develop intervention packages to facilitate PrEP adherence among Chinese key populations using co-creation methods. The study will then evaluate the efficacy of the co-created intervention packages using a stepped-wedge randomized controlled trial. This four-phased closed cohort stepped-wedge design will have four clusters. Each cluster will start intervention at three-month intervals. Seven hundred participants who initiated PrEP will be recruited. Participants will be randomized to the clusters using block randomization. The intervention condition includes receiving co-created interventions in addition to standard of care. The control condition is the standard of care that includes routine clinical assessment every 3 months. All participants will also receive an online follow-up survey every 3 months to record medication adherence and will be encouraged to use a WeChat mini-app for sexual and mental health education throughout the study. The primary outcomes are PrEP adherence and retention in PrEP care throughout the study period. We will examine a hypothesis that a co-created intervention can facilitate PrEP adherence. Generalized linear mixed models will be used for the primary outcome analysis. Discussion Developing PrEP adherence interventions in China faces barriers including suboptimal PrEP uptake among key populations, the lack of effective PrEP service delivery models, and insufficient community engagement in PrEP initiatives. Our study design addresses these obstacles by using co-creation to generate social media-based intervention materials and embedding the study design in the local healthcare system. The study outcomes may have implications for policy and intervention practices among CBOs and the medical system to facilitate PrEP adherence among key populations. Trial registration The study is registered in Clinical Trial databases in China (ChiCTR2100048981, July 19, 2021) and the US (NCT04754139, February 11, 2021).

A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site. In the present study, we achieved an enriched concentration of PD-L1 from exosomes (Exos) of a genetically engineered Human Umbilical Vein Endothelial Cell (HUVECs), and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface, suppressing the activation of T cells. Furthermore, exosomal PD-L1 induced Mesenchymal Stem Cells (MSCs) towards osteogenic differentiation when pre-cultured with T cells. Moreover, embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner. Additionally, exosomal PD-L1, embedded in a hydrogel, markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase. Importantly, our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites, while T cells in distant immune organs such as the spleen were not affected. In summary, this study provides the first example of using PD-L1-enriched Exos for bone fracture repair, and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.

Directional axon regeneration and remyelination are crucial for repair of spinal cord injury (SCI), but existing treatments do not effectively promote those processes. Here, we propose a strategy for construction of niche-specific spinal white matter-like tissue (WMLT) using decellularized optic nerve (DON) loaded with neurotrophin-3 (NT-3)-overexpressing oligodendrocyte precursor cells. A rat model with a white matter defect in the dorsal spinal cord of the T10 segment was used. The WMLT transplantation group showed significant improvement in coordinated motor functions compared with the control groups. WMLT transplants integrated well with host spinal cord white matter, effectively addressing several barriers to directional axonal regeneration and myelination during SCI repair. In WMLT, laminin was found to promote development of oligodendroglial lineage (OL) cells by binding to laminin receptors. Interestingly, laminin could also guide linear axon regeneration via interactions with specific integrins on the axon surface. The WMLT developed here utilizes the unique microstructure and bioactive matrix of DON to create a niche rich in laminin, NT-3 and OL cells to achieve significant structural repair of SCI. Our protocol can help to promote research on repair of nerve injury and construction of neural tissues and organoids that form specific cell niches.

The Coronavirus Disease 2019 (COVID-19) pandemic has been estimated to have claimed more than 6 million lives, and most deaths have been attributed to complications non-specific to the virus. Therefore, understanding and treating these complications are imperative. In this meta-analysis, we reviewed 181 studies published in early stages of the COVID-19 pandemic. We presented that the complications with high incidence among all COVID-19 cases were acute respiratory distress syndrome (ARDS, 18.52%), respiratory failure (16.54%), liver injury (14.13%) and multiple-organ dysfunction syndrome (MODS, 13.62%). Among patients who died, the most common complications were ARDS (84.10%), respiratory failure (78.75%) and respiratory injury (75.72%). Subsequently, we analyzed the risk factors for complications, and reviewed the currently available therapies according to complications and prognosis. To decrease the prevalence of COVID-19 complications and mortality, healthcare workers and patients should pay greater attention to the complications identified herein, particularly those occurring preclinically.

Abstract Background We aimed to compare the intraoperative and early postoperative clinical outcomes of using an acromioclavicular joint hook plate (AJHP) versus a locking plate (LP) in the treatment of anterior sternoclavicular joint dislocation. Methods Seventeen patients with anterior sternoclavicular joint dislocation were retrospectively analyzed from May 2014 to September 2019. Six patients were surgically treated with an AJHP, and 11 were surgically treated with an LP. Five male and one female patients composed the AJHP group, and nine male and two female patients composed the LP group. The mean age of all patients was 49.5 years. Results Reduction and fixation were performed with AJHP or LP in all 17 patients. The mean operative blood loss, operative time, and length of incision in the AJHP group were significantly better than those in the LP group. Shoulder girdle movement of the AJHP group was significantly better than that of the LP group. Conclusions This study revealed that AJHP facilitated glenohumeral joint motion, reduced the risk of rupture of mediastinal structures, required a shorter incision, and had lesser blood loss and a shorter duration of operation compared with LP. However, some deficiencies require further improvement.

Abstract The selection and training of aircraft pilots has high standards, long training cycles, high resource consumption, high risk, and high elimination rate. It is the particularly urgent and important requirement for the current talent training strategy of national and military to increase efficiency and speed up all aspects of pilot training, reduce the training cycle and reduce the elimination rate. To this end, this paper uses deep variational auto-encoder network and adaptive dynamic time warping algorithms as support to explore the establishment of an integrated evaluation system for flight maneuver recognition and quality evaluation, solve the industry difficulty faced by current flight training data mining applications, and achieve accurate recognition and reliable quality evaluation of flight regimes under the background of high mobility. It will fully explore the benefits of existing airborne flight data for military trainee pilots, support the personalized and accurate training of flight talents, and reduce the rate of talent elimination.

IntroductionIn the context of an aging population and age-related conditions increasing, the increasing number of middle-aged and older adults are involved in grandchildren care. This study aimed to 1) explore the association between caring for grandchildren based on living arrangements and cognitive function among Chinese middle-aged and older adults; and 2) investigate the mediating roles of social activities and depressive symptoms in the aforementioned association.MethodsThis study selected 5490 Chinese people (≥45 years old) from the 2018 China Health and Retirement Longitudinal Study (CHARLS). Participants answered questions related to socio-demographics, the Mini-mental State Examination, the intensity of grandchildren care, the Center for Epidemiological Studies Depression Scale, and social activity.ResultsThe results showed that caring for grandchildren and cohabiting with a spouse was positively associated with cognitive function among Chinese middle-aged and older adults (B = 0.829, p < 0.001). Furthermore, there was a positive association between providing intensive or no-intensive grandchildren care and cognitive function. In contrast, caring for grandchildren but not cohabiting with a spouse was negatively associated with cognitive function (B = −0.545, p < 0.05). Moreover, directly and indirectly, caring for grandchildren was significantly associated with cognitive function among Chinese middle-aged and older adults, as mediated by social activities and depressive symptoms.DiscussionThe findings emphasize that living arrangements, social engagement, and psychological health could be considered when encouraging grandparent care as formal care.

BackgroundMobile 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).MethodsWe 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.ResultsBetween 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.ConclusionsThis 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 registrationTrial registration: The study was prospectively registered on clinicaltrials.gov (NCT04426656) on 11 June, 2020.

The increasingly aging society led to a rise in the prevalence of chronic wounds (CWs), posing a significant burden to public health on a global scale. One of the key features of CWs is the presence of a maladjusted immune microenvironment characterized by persistent and excessive (hyper)inflammation. A variety of immunomodulatory therapies have been proposed to address this condition. Yet, to date, current delivery systems for immunomodulatory therapy remain inadequate and lack efficiency. This highlights the need for new therapeutic delivery systems, such as nanosystems, to manage the pathological inflammatory imbalance and, ultimately, improve the treatment outcomes of CWs. While a plethora of immunomodulatory nanosystems modifying the immune microenvironment of CWs have shown promising therapeutic effects, the literature on the intersection of immunomodulatory nanosystems and CWs remains relatively scarce. Therefore, this review aims to provide a comprehensive overview of the pathogenesis and characteristics of the immune microenvironment in CWs, discuss important advancements in our understanding of CW healing, and delineate the versatility and applicability of immunomodulatory nanosystems-based therapies in the therapeutic management of CWs. In addition, we herein also shed light on the main challenges and future perspectives in this rapidly evolving research field.

Bone mesenchymal stem cells (BMSCs) play an important role in maintaining the dynamic balance of bone metabolism. Recent studies have reported that a decrease in the osteogenic function of MSCs is strongly associated with osteoporosis. Melatonin is a neuroendocrine hormone produced in the pineal gland and is essential in the physiological regulation. This study is aimed at exploring the effect of melatonin on MSCs osteoblastic differentiation and elucidate the underlying mechanisms. We isolated BMSCs from rat bone marrow and demonstrated that melatonin improved osteogenic differentiation of BMSCs by the alizarin red staining and ALP staining. We then showed that melatonin enhanced osteogenic gene expression in BMSCs, including ALP, Col 1, OCN, OPN, and RUNX2. We further revealed that melatonin inhibited the inflammatory response of BMSCs by suppressing the NF-κB signaling pathways. In light of this, we found that the NF-κB pathway-specific activator TNF-α activated the NF-κB pathway, inhibited osteogenic differentiation, and induced inflammatory response in BMSCs. Melatonin was found to reverse the inhibitory effect of TNF-α on osteogenic differentiation and inflammation in BMSCs. Taken together, these findings indicated that melatonin may have therapeutic potential to be used for the treatment of osteoporosis.

As bone biology develops, it is gradually recognized that bone regeneration is a pathophysiological process that requires the simultaneous participation of multiple systems. With the introduction of osteoimmunology, the interplay between the immune system and the musculoskeletal diseases has been the conceptual framework for a thorough understanding of both systems and the advancement of osteoimmunomodulaty biomaterials. Various therapeutic strategies which include intervention of the surface characteristics or the local delivery systems with the incorporation of bioactive molecules have been applied to create an ideal bone microenvironment for bone tissue regeneration. Our review systematically summarized the current research that is being undertaken in the field of osteoimmunomodulaty bone biomaterials on a case-by-case basis, aiming to inspire more extensive research and promote clinical conversion.

Extensive research has implicated inflammation and oxidative stress in the development of multiple diseases, such as diabetes, hepatitis, and arthritis. Kinsenoside (KD), a bioactive glycoside component extracted from the medicinal plant Anoectochilus roxburghii, has been shown to exhibit potent anti-inflammatory and anti-oxidative abilities. In this review, we summarize multiple effects of KD, including hepatoprotection, pro-osteogenesis, anti-hyperglycemia, vascular protection, immune regulation, vision protection, and infection inhibition, which are partly responsible for suppressing inflammation signaling and oxidative stress. The protective action of KD against dysfunctional lipid metabolism is also associated with limiting inflammatory signals, due to the crosstalk between inflammation and lipid metabolism. Ferroptosis, a process involved in both inflammation and oxidative damage, is potentially regulated by KD. In addition, we discuss the physicochemical properties and pharmacokinetic profiles of KD. Advances in cultivation and artificial synthesis techniques are promising evidence that the shortage in raw materials required for KD production can be overcome. In addition, novel drug delivery systems can improve the in vivo rapid clearance and poor bioavailability of KD. In this integrated review, we aim to offer novel insights into the molecular mechanisms underlying the therapeutic role of KD and lay solid foundations for the utilization of KD in clinical practice.

BackgroundPrimary mucinous lung adenocarcinoma, a subtype of lung adenocarcinoma, is extremely rare. Currently, as there are no specific diagnostic features, it is easy to delay the diagnosis or even to misdiagnose when atypical symptoms are present.Case summaryThis case details a patient with primary mucinous lung adenocarcinoma and metastasis to the femoral head. The sole symptom was left hip pain and the initial diagnosis was isolated femoral head necrosis.ConclusionsBy presenting this rare case report and the experiences learned from it, we hope to assist clinicians to identify bone metastasis cases with non-typical symptoms in order to make the correct diagnosis as soon as possible.

BackgroundA coronal comminuted femoral intertrochanteric fracture is a special type of fracture that easily leads to internal fixation failure, and the current internal fixation techniques remain controversial. This study aims to evaluate the effect of traction-bed-assisted reduction and double-plate internal fixation in the treatment of comminuted and coronally split intertrochanteric femoral fracture.MethodRetrospective analyses of the clinical data of 83 patients diagnosed with, and treated for, comminuted and coronally split intertrochanteric femoral fracture from December 2017 to November 2019 were conducted. Among the total number of 83 patients, 40 patients received traction-bed-assisted reduction and PFNA fixation (the control group), whereas 43 patients received traction-bed-assisted reduction and double-plate internal fixation (the experimental group). The major indicators for the research analysis such as the general information of patients, perioperative data, and follow-up data of both groups were collected, sorted out, and meticulously analyzed.ResultsThe time taken for traction-bed-assisted reduction and double-plate intern fixation in the experimental group was significantly shorter than that in the control group (P .05).ConclusionThe use of a traction bed to achieve adequate reduction, followed by internal fixation using double plates, comparatively takes less time for both reduction and operation in the treatment of comminuted and coronally split intertrochanteric femoral fractures, which also restores proper hip joint movements relatively early and hence provides better hip joint functions in the long run.

Abstract The main proteases (Mpro), also termed 3‐chymotrypsin‐like proteases (3CLpro), are a class of highly conserved cysteine hydrolases in β‐coronaviruses. Increasing evidence has demonstrated that 3CLpros play an indispensable role in viral replication and have been recognized as key targets for preventing and treating coronavirus‐caused infectious diseases, including COVID‐19. This review is focused on the structural features and biological function of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease Mpro (also known as 3CLpro), as well as recent advances in discovering and developing SARS‐CoV‐2 3CLpro inhibitors. To better understand the characteristics of SARS‐CoV‐2 3CLpro inhibitors, the inhibition activities, inhibitory mechanisms, and key structural features of various 3CLpro inhibitors (including marketed drugs, peptidomimetic, and non‐peptidomimetic synthetic compounds, as well as natural compounds and their derivatives) are summarized comprehensively. Meanwhile, the challenges in this field are highlighted, while future directions for designing and developing efficacious 3CLpro inhibitors as novel anti‐coronavirus therapies are also proposed. Collectively, all information and knowledge presented here are very helpful for understanding the structural features and inhibitory mechanisms of SARS‐CoV‐2 3CLpro inhibitors, which offers new insights or inspiration to medicinal chemists for designing and developing more efficacious 3CLpro inhibitors as novel anti‐coronavirus agents.

Tea plantations encroachment into forests has occurred in the major tea planting area of Yunnan province, China in the past decades. However, the dynamics of tea plantation encroachment into forests and the effect on forest landscape pattern is not clear. In this study, we proposed a method to evaluate the dynamic effects of tea plantation encroachment on forest landscape pattern change by using time series Landsat 5/7/8 data from 1991 to 2021 on the Google Earth Engine (GEE) platform. First, a pixel- and phenology-based algorithm was applied to generate tea plantations encroachment into forests maps for seven historical periods. Second, three indices including the tea plantations encroachment index (TPEI), the growth area of tea plantations encroachment into forests (GATEF), and the growth index of tea plantations encroachment into forests (GITEF) were used to quantify the tea plantations encroachment into forests of seven historical periods. Third, the effects of forests landscape pattern resulting from tea plantations encroachment were evaluated in class metrics and landscape metrics respectively. Our results show a total of 13,721 ha of GATEF from the early 1990s to the early 2020s. The GITEF increased from the early 1990s to the early 2010s and decreased from the early 2010s to the early 2020s in our study area. And the TPEI indicates that the edge encroachment mode dominated in our study period. Correlation analysis indicates that tea plantations encroachment level had significant correlation coefficients with landscape pattern indices (such as CONTAG (r = −0.91), ED (r = 0.95), DIVISION (r = 0.85), and SHEI (r = 0.86)), which indicates that the level of tea plantations encroachment affects significantly the forest landscape pattern. This study provides a promising approach to quantifying the effect of forest landscape pattern results from tea plantations encroachment.

Cell senescence is a crucial process in cell fate determination and is involved in an extensive array of aging-associated diseases. General perceptions and experimental evidence point out that the decline of physical function as well as aging-associated diseases are often initiated by cell senescence and organ ageing. Therefore, regulation of cell senescence process can be a promising way to handle aging-associated diseases such as osteoporosis. The circadian clock regulates a wide range of cellular and physiological activities, and many age-linked degenerative disorders are associated with the dysregulation of clock genes. BMAL1 is a core circadian transcription factor and governs downstream genes by binding to the E-box elements in their promoters. Compelling evidence has proposed the role of BMAL1 in cellular senescence and aging-associated diseases. In this review, we summarize the linkage between BMAL1 and factors of cell senescence including oxidative stress, metabolism, and the genotoxic stress response. Dysregulated and dampened BMAL1 may serve as a potential therapeutic target against aging- associated diseases.

Objective: To examine the psychometric properties of four common hamstring muscle flexibility tests involving the straight leg raise (SLR), passive knee extension (PKE), sit and reach test (SRT) and toe touch test (TTT) in young adults.Methods: Forty-three young healthy adults (mean age 27.4 years) were recruited for 3 repeated sessions of hamstring flexibility assessments using the 4 tests mentioned above and the subsequent isokinetic examinations. The first two sessions (S1 and S2) were conducted by two different raters randomly on the first day (D1), and the third session (S3) was conducted by the same rater as S1 3 days later (D4). The next day (D5), the isokinetic performances of knee extensors and flexors of the dominant leg were assessed. To evaluate the interrater (S1 vs. S2) and test-retest (S1 vs. S3) reliability of hamstring flexibility tests, intraclass correlation coefficients (ICCs), standard errors of measurement, and the minimum detectable differences were calculated. Correlation analyses were performed to study the association of each hamstring flexibility test with the isokinetic muscle function of the knee flexors (H) and extensors (Q), including the peak torque (PT), total amount of work (TW) and average power (AP).Results: Excellent interrater and test-retest reliability of hamstring flexibility tests involving the SLR, PKE, SRT and TTT were confirmed with ICCs ranging from 0.923 to 0.986. Fair correlations were found between the 4 hamstring flexibility tests and the H/Q for the PT at angular speeds of 180°/s (Pearson’s r at 0.330–0.449). In addition, the PKE was fairly correlated with the AP of the hamstring (Pearson’s r = 0.320) and the H/Q for the TW (Pearson’s r = 0.345) and AP (Pearson’s r = 0.386) at angular speeds of 180°/s.Conclusions: This study confirmed that the SLR, PKE, SRT and TTT were reliable flexibility tests for hamstring muscles in young healthy adults, and the PKE might be a more valid outcome measure to predict hamstring injury.

Abstract Background Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing. Results We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing. Conclusions PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing. Graphic abstract

Patients who sustain concomitant fractures and traumatic brain injury (TBI) are known to have significantly quicker fracture-healing rates than patients with isolated fractures. The mechanisms underlying this phenomenon have yet to be identified. In the present study, we found that the upregulation of microRNA-92a-3p (miRNA-92a-3p) induced by TBI correlated with a decrease in integrin binding sialoprotein (IBSP) expression in callus formation. In vitro, overexpressing miRNA-92a-3p inhibited IBSP expression and accelerated osteoblast differentiation, whereas silencing of miRNA-92a-3p inhibited osteoblast activity. A decrease in IBSP facilitated osteoblast differentiation via the Phosphatidylinositol 3-kinase/threonine kinase 1 (PI3K/AKT) signaling pathway. Through luciferase assays, we found evidence that IBSP is a miRNA-92a-3p target gene that negatively regulates osteoblast differentiation. Moreover, the present study confirmed that pre-injection of agomiR-92a-3p leads to increased bone formation. Collectively, these results indicate that miRNA-92a-3p overexpression may be a key factor underlying the improved fracture healing observed in TBI patients. Upregulation of miRNA-92a-3p may therefore be a promising therapeutic strategy for promoting fracture healing and preventing nonunion.

Introduction The large number of key populations in China who would benefit from HIV pre-exposure prophylaxis (PrEP) in the context of limited health system capacity and public awareness will pose challenges for timely PrEP scale-up, suggesting an urgent need for innovative and accessible interventions. This study aims to develop and pilot test a theory-informed, tailored mobile phone intervention that was codeveloped by young gay men, HIV clinicians and public health researchers to increase engagement in PrEP education and initiation among Chinese gay, bisexual and other men who have sex with men (GBMSM), who bear a disproportionate burden of HIV infections and remain underserved in the healthcare system.Methods and analysis This two-phase study includes a formative assessment using in-depth interviews (N=30) and a 12-week experimental pilot study using a two-arm randomised controlled trial design (N=70). The primary intervention is delivered through a WeChat-based mini-app (a program built into a Chinese multipurpose social media application) developed by young GBMSM from a 2019 crowdsourcing hackathon. Using mixed methods, we will further investigate the specific needs and concerns among GBMSM in terms of using PrEP as an HIV prevention strategy, how their concerns and PrEP use behaviours may change with exposure to the mini-app intervention during the study period and how we can further refine this intervention tool to better meet GBMSM’s needs for broader implementation.Ethics and dissemination This study and its protocols have been reviewed and approved by the Institutional Review Boards of the University of North Carolina at Chapel Hill, USA (19-3481), the Guangdong Provincial Dermatology Hospital, China (2020031) and the Guangzhou Eighth People’s Hospital, China (202022155). Study staff will work with local GBMSM community-based organisations to disseminate the study results to participants and the community via social media, workshops and journal publications.Trial registration number The study was prospectively registered on clinicaltrials.gov (NCT04426656) on 11 June 2020.

Background and purpose — Following the outbreak of COVID-19 in December 2019, in China, many hip fracture patients were unable to gain timely admission and surgery. We assessed whether delayed surgery improves hip joint function and reduces major complications better than nonoperative therapy. Patients and methods — In this retrospective observational study, we collected data from 24 different hospitals from January 1, 2020, to July 20, 2020. 145 patients with hip fractures aged 65 years or older were eligible. Clinical data was extracted from electronic medical records. The primary outcomes were visual analogue scale (VAS) score and Harris Hip Score. Major complications, including deep venous thrombosis (DVT) and pneumonia within 1 month and 3 months, were collected for further analysis. Results — Of the 145 hip fracture patients 108 (median age 72; 70 females) received delayed surgery and 37 (median age 74; 20 females) received nonoperative therapy. The median time from hip fracture injury to surgery was 33 days (IQR 24–48) in the delayed surgery group. Hypertension, in about half of the patients in both groups, and cerebral infarction, in around a quarter of patients in both groups, were the most common comorbidities. Both VAS score and Harris Hip Score were superior in the delayed surgery group. At the 3-month follow-up, the median VAS score was 1 in the delayed surgery group and 2.5 in the nonoperative group (p < 0.001). Also, the percentage of complications was higher in the nonoperative group (p = 0.004 for DVT, p < 0.001 for pulmonary infection). Interpretation — In hip fracture patients, delayed surgery compared with nonoperative therapy significantly improved hip function and reduced various major complications.

Mesenchymal stem cells (MSCs) critically contribute to bone formation, and proper induction of osteogenic differentiation can lead to an increase in bone mass. In the present study, we reported that an increased miR-194-5p level in plasma is inversely related to the degree of bone formation in osteoporosis patients. We also noted that increased miR-194-5p in the MSCs of ovariectomized (OVX) mice and agomiR-194-5p manipulation of miR-194-5p significantly suppressed bone formation, both in aged and OVX mice. Furthermore, our in vitro study showed that overexpression of miR-194-5p suppresses osteogenic differentiation, as evidenced by the decreased bone formation marker genes and matrix mineralization. The luciferase assay indicated that Wnt family member 5a (Wnt5a) is a target gene of miR-194-5p that positively regulates osteogenic differentiation. Collectively, these data indicated that miR-194-5p inhibition may be a potential strategy for osteoporosis prevention.

Abstract Background Hepatitis C virus (HCV) is a growing public health problem with a large disease burden worldwide. In China many people living with HCV are unaware of their hepatitis status and not connected to care and treatment. Crowdsourcing is a technique that invites the public to create health promotion materials and has been found to increase HIV testing uptake, including in China. This trial aims to evaluate crowdsourcing as a strategy to improve HCV awareness, testing and linkage-to-care in China. Methods A randomized controlled, two-armed trial (RCT) is being conducted in Shenzhen with 1006 participants recruited from primary care sectors of The University of Hong Kong-Shenzhen Hospital. Eligible participants are ≥30 years old; a resident in Shenzhen for at least one month after recruitment; no screening for HCV within the past 12 months and not known to have chronic HCV; and, having a WeChat social media account. Allocation is 1:1. Both groups will be administered a baseline and a follow-up survey (4-week post-enrollment). The intervention group will receive crowdsourcing materials to promote HCV testing once a week for two weeks and feedback will be collected thereafter, while the control group will receive no promotional materials. Feedback collected will be judged by a panel and selected to be implemented to improve the intervention continuously. Those identified positive for HCV antibodies will be referred to gastroenterologists for confirmation and treatment. The primary outcome will be confirmed HCV testing uptake, and secondary outcomes include HCV confirmatory testing and initiation of HCV treatment with follow-ups with specialist providers. Data will be collected on Survey Star@ via mobile devices. Discussion This will be the first study to evaluate the impact of crowdsourcing to improve viral hepatitis testing and linkage-to-care in the health facilities. This RCT will contribute to the existing literature on interventions to improve viral hepatitis testing in primary care setting, and inform future strategies to improve HCV care training for primary care providers in China. Trial registration Chinese Clinical Trial Registry. ChiCTR1900025771. Registered September 7th, 2019, http://www.chictr.org.cn/showprojen.aspx?proj=42788