Mesenchymal stromal cells suppress microglial activation and tumor necrosis factor production.

BACKGROUND AIMS: White matter diseases are commonly associated with microglial activation and neuroinflammation. Mesenchymal stromal cells (MSCs) have immunomodulatory properties and thus have the potential to be developed as cell therapy for white matter disease. MSCs interact with resident macrophages to alter the trajectory of inflammation; however, the impact MSCs have on central nervous system macrophages and the effect this has on the progression of white matter disease are unclear. METHODS: In this study, we utilized numerous assays of varying complexity to model different aspects of white matter disease. These assays ranged from an in vivo spinal cord acute demyelination model to a simple microglial cell line activation assay. Our goal was to investigate the influence of human umbilical cord tissue MSCs on the activation of microglia. RESULTS: MSCs reduced the production of tumor necrosis factor (TNF) by microglia and decreased demyelinated lesions in the spinal cord after acute focal injury. To determine if MSCs could directly suppress the activation of microglia and to develop an efficient potency assay, we utilized isolated primary microglia from mouse brains and the Immortalized MicroGlial Cell Line (IMG). MSCs suppressed the activation of microglia and the release of TNF after stimulation with lipopolysaccharide, a toll-like receptor agonist. CONCLUSIONS: In this study, we demonstrated that MSCs altered the immune response after acute injury in the spinal cord. In numerous assays, MSCs suppressed activation of microglia and release of the pro-inflammatory cytokine TNF. Of these assays, IMG could be standardized and used as an effective potency assay to determine the efficacy of MSCs for treating white matter disease or other neuroinflammatory conditions associated with microglial activation.

The musculoskeletal syndrome of menopause.

Fifty-one percent of humans are born with ovaries. As the ovarian production of estrogen diminishes in midlife and ultimately stops, it is estimated that more than 47 million women worldwide enter the menopause transition annually. More than 70% will experience musculoskeletal symptoms and 25% will be disabled by them through the transition from perimenopause to postmenopause. This often-unrecognized collective of musculoskeletal symptoms, largely influenced by estrogen flux, includes arthralgia, loss of muscle mass, loss of bone density and progression of osteoarthritis, among others. In isolation, it can be difficult for clinicians and patients to adequately appreciate the substantial role of decreasing estrogen, anticipate the onset of related symptoms and actively treat to mitigate future detrimental processes. Thus, in this review we introduce a new term, the musculoskeletal syndrome of menopause, to describe the collective musculoskeletal signs and symptoms associated with the loss of estrogen. Given the significant effects of these processes on quality of life and the associated personal and financial costs, it is important for clinicians and the women they care for to be aware of this terminology and the constellation of musculoskeletal processes for which proper risk assessment and prophylactic management are of consequence.

Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection.

The human skeleton is a metabolically active system that is constantly regenerating via the tightly regulated and highly coordinated processes of bone resorption and formation. Emerging evidence reveals fascinating new insights into the role of sphingolipids, including sphingomyelin, sphingosine, ceramide, and sphingosine-1-phosphate, in bone homeostasis. Sphingolipids are a major class of highly bioactive lipids able to activate distinct protein targets including, lipases, phosphatases, and kinases, thereby conferring distinct cellular functions beyond energy metabolism. Lipids are known to contribute to the progression of chronic inflammation, and notably, an increase in bone marrow adiposity parallel to elevated bone loss is observed in most pathological bone conditions, including aging, rheumatoid arthritis, osteoarthritis, and osteomyelitis. Of the numerous classes of lipids that form, sphingolipids are considered among the most deleterious. This review highlights the important primary role of sphingolipids in bone homeostasis and how dysregulation of these bioactive metabolites appears central to many chronic bone-related diseases. Further, their contribution to the invasion, virulence, and colonization of both viral and bacterial host cell infections is also discussed. Many unmet clinical needs remain, and data to date suggest the future use of sphingolipid-targeted therapy to regulate bone dysfunction due to a variety of diseases or infection are highly promising. However, deciphering the biochemical and molecular mechanisms of this diverse and extremely complex sphingolipidome, both in terms of bone health and disease, is considered the next frontier in the field.

Multivariate Analysis of Risk Factors for Injury and Surgical Interventions in Ankle and Knee Injuries in NBA Athletes.

Objective: Lower extremity ankle and knee injuries occur at a high rate in the National Basketball Association (NBA) often requiring surgical intervention. This study aimed to identify surgical rates and risk factors for surgical intervention using multivariate analysis in ankle and knee injuries in NBA player. Methods: Player demographics, performance metrics, advanced statistics, and injury characteristics were recorded using publicly available data. To standardize injury events over multiple years, injury events per 1000 athlete exposure events (AE, one player participating in one game) were calculated. Descriptive analysis and multivariate logistic regression were completed to find associations with surgical intervention in ankle and knee injuries. Results: A total of 1153 ankle and knee injuries were included in the analysis with 73 (6.33%) lower extremity injuries treated with surgery. Knee injuries had a higher incidence of surgical intervention (0.23 AE) than ankle injuries (0.04 AE). The most frequent surgical knee injury was meniscus tear treated with meniscus repair (0.05 AE) and the most frequent ankle surgery was surgical debridement (0.01 AE) Multivariate logistic regression indicated lower extremity injuries that required surgery were associated with more minutes per game played (odds ratio [OR] 1.13; p = 0.02), a greater usage rate (OR 1.02 p < 0.001), the center position (OR 1.64; 95% [CI] 1.2-2.24; p = 0.002) and lower player efficiency rating (OR 0.96; 95% p < 0.001). Conclusion: Knee surgery was significantly more frequent than ankle surgery despite similar injury rates per 1000 exposures. The center position had the greatest risk for lower extremity injury followed by minutes played while a higher player efficiency rating was protective against surgical intervention. Developing strategies to address these factors will help in the management and prevention of lower extremity injuries requiring surgical intervention.

Mechanism of Knee Injuries in the National Basketball Association: A Video-Based Analysis.

Background: To characterize the mechanism of knee injuries among NBA players during the 2010-2020 seasons using video-based analysis. Methods: An injury database of NBA players was queried for knee injuries from the 2006-07 to 2020-21 seasons and cross-referenced with NBA injury reports. Youtube.com was searched to identify available injury footage. The mechanism of knee injury during play was analyzed by three independent reviewers. Non-mechanistic data related to the injury was gathered from news reports and official NBA websites. Results: A total of 2,868 knee injuries occurred in NBA players from 2010 to 2020 seasons; 121 had high quality videos for analysis. The most common mechanism of injury was knee flexion in valgus with internal rotation (27.3%, p < 0.001), which was associated with injury to the ACL (55.2%, p=0.0001). Injuries occurred most often with control of the ball (62.8%, p=0.0064), while on offense (73.6%, p=0.0001), and without contact (71.1%, p=0.0001). A 28.1% incidence of re-injury was observed in the first 3-year period, and 43.8% of knee injuries required surgery. The average number of games missed due to injury requiring surgery was 55.1 games compared to 8.5 games in those treated nonoperatively (p < 0.0001). Conclusion: Understanding mechanisms of knee injury may guide preventative strategies and injury management programs in NBA players. Video-based analysis reveals the situational characteristics and mechanisms of knee injuries, but further studies are needed to develop injury prevention programs, efficacy of prevention strategies, and rehabilitation to minimize games missed from these injuries.

Emerging Medical Technologies and Their Use in Bionic Repair and Human Augmentation.

As both the proportion of older people and the length of life increases globally, a rise in age-related degenerative diseases, disability, and prolonged dependency is projected. However, more sophisticated biomedical materials, as well as an improved understanding of human disease, is forecast to revolutionize the diagnosis and treatment of conditions ranging from osteoarthritis to Alzheimer's disease as well as impact disease prevention. Another, albeit quieter, revolution is also taking place within society: human augmentation. In this context, humans seek to improve themselves, metamorphosing through self-discipline or more recently, through use of emerging medical technologies, with the goal of transcending aging and mortality. In this review, and in the pursuit of improved medical care following aging, disease, disability, or injury, we first highlight cutting-edge and emerging materials-based neuroprosthetic technologies designed to restore limb or organ function. We highlight the potential for these technologies to be utilized to augment human performance beyond the range of natural performance. We discuss and explore the growing social movement of human augmentation and the idea that it is possible and desirable to use emerging technologies to push the boundaries of what it means to be a healthy human into the realm of superhuman performance and intelligence. This potential future capability is contrasted with limitations in the right-to-repair legislation, which may create challenges for patients. Now is the time for continued discussion of the ethical strategies for research, implementation, and long-term device sustainability or repair.

Multifunctional scaffolds for bone repair following age-related biological decline: Promising prospects for smart biomaterial-driven technologies.

The repair of large bone defects due to trauma, disease, and infection can be exceptionally challenging in the elderly. Despite best clinical practice, bone regeneration within contemporary, surgically implanted synthetic scaffolds is often problematic, inconsistent, and insufficient where additional osteobiological support is required to restore bone. Emergent smart multifunctional biomaterials may drive important and dynamic cellular crosstalk that directly targets, signals, stimulates, and promotes an innate bone repair response following age-related biological decline and when in the presence of disease or infection. However, their role remains largely undetermined. By highlighting their mechanism/s and mode/s of action, this review spotlights smart technologies that favorably align in their conceivable ability to directly target and enhance bone repair and thus are highly promising for future discovery for use in the elderly. The four degrees of interactive scaffold smartness are presented, with a focus on bioactive, bioresponsive, and the yet-to-be-developed autonomous scaffold activity. Further, cell- and biomolecular-assisted approaches were excluded, allowing for contemporary examination of the capabilities, demands, vision, and future requisites of next-generation biomaterial-induced technologies only. Data strongly supports that smart scaffolds hold significant promise in the promotion of bone repair in patients with a reduced osteobiological response. Importantly, many techniques have yet to be tested in preclinical models of aging. Thus, greater clarity on their proficiency to counteract the many unresolved challenges within the scope of aging bone is highly warranted and is arguably the next frontier in the field. This review demonstrates that the use of multifunctional smart synthetic scaffolds with an engineered strategy to circumvent the biological insufficiencies associated with aging bone is a viable route for achieving next-generation therapeutic success in the elderly population.

Extracellular Proteins Isolated from L. acidophilus as an Osteomicrobiological Therapeutic Agent to Reduce Pathogenic Biofilm Formation, Regulate Chronic Inflammation, and Augment Bone Formation In Vitro.

Periprosthetic joint infection (PJI) is a challenging complication that can occur following joint replacement surgery. Efficacious strategies to prevent and treat PJI and its recurrence remain elusive. Commensal bacteria within the gut convey beneficial effects through a defense strategy named "colonization resistance" thereby preventing pathogenic infection along the intestinal surface. This blueprint may be applicable to PJI. The aim is to investigate Lactobacillus acidophilus spp. and their isolated extracellular-derived proteins (LaEPs) on PJI-relevant Staphylococcus aureus, methicillin-resistant S. aureus, and Escherichia coli planktonic growth and biofilm formation in vitro. The effect of LaEPs on cultured macrophages and osteogenic, and adipogenic human bone marrow-derived mesenchymal stem cell differentiation is analyzed. Data show electrostatically-induced probiotic-pathogen species co-aggregation and pathogenic growth inhibition together with LaEP-induced biofilm prevention. LaEPs prime macrophages for enhanced microbial phagocytosis via cathepsin K, reduce lipopolysaccharide-induced DNA damage and receptor activator nuclear factor-kappa B ligand expression, and promote a reparative M2 macrophage morphology under chronic inflammatory conditions. LaEPs also significantly augment bone deposition while abating adipogenesis thus holding promise as a potential multimodal therapeutic strategy. Proteomic analyses highlight high abundance of lysyl endopeptidase, and urocanate reductase. Further, in vivo analyses are warranted to elucidate their role in the prevention and treatment of PJIs.

Performance of Orthopaedic Shoulder and Elbow Surgeons on a Biostatistical Knowledge Examination.

Background: The objective of this study is to evaluate the biostatistical interpretation abilities of fellowship trained orthopaedic surgeons. Methods: A cross-sectional survey was administered to orthopaedic surgeon members of the American Shoulder and Elbow Surgeons (ASES), assessing orthopaedic surgeon attitudes towards biostatistics, confidence in understanding biostatistics, and ability to interpret biostatistical measures on a multiple-choice test. Results: A 4.5% response rate was achieved with 55 complete survey responses. The mean percent correct was 55.2%. Higher knowledge test scores were associated with younger age and fewer years since board exam completion (p ≤ 0.001). Greater average number of publications per year correlated with superior statistical interpretation (p=0.009). Respondents with higher self-reported confidence were more likely to accurately interpret results (p ≤ 0.017). Of the respondents, 93% reported frequently using statistics to form medical opinions, 98% answered that statistical competency is important in the practice of orthopaedic surgery, and 80% were eager to continue learning biostatistics. Conclusions: It is concerning that fellowship-trained shoulder and elbow surgeons, many of whom frequently publish or are reviewing scientific literature for publication, are scoring 55.2% correctly on average on this biostatistical knowledge examination. Surgeons that are further from formal statistical knowledge training are more likely to have lower biostatistical knowledge test scores. Respondents who published at the highest rate were associated with higher scores. Continuing medical education in biostatistics may be beneficial for maintaining statistical knowledge utilised in the current literature.

Positive Correlation Between Social Media Utilization by Orthopaedic Journals and Impact Factor.

INTRODUCTION: Social media use has exploded in popularity over the past decade with over 1.5 billion users on Facebook and 320 million users on Twitter. The aim of this study was to analyze the use of social media by orthopaedic journals and determine whether a relationship exists between social media followers and journal impact factor. METHODS: The Clarivate Analytics Impact Factor tool was used to identify all orthopaedic journals with a 2022 impact factor of greater than 1.5. We then conducted a query on Instagram, Twitter, LinkedIn, and Facebook to determine which programs had pages on each platform. RESULTS: Seventeen journals were included across all orthopaedic subspecialties. Of the 17 journals, 14 (82.4%) had a Facebook page, eight (47%) had an Instagram page, 15 (88.2%) had a Twitter account, and 8 (47%) had a LinkedIn profile. When compiling the number of followers by social media platform, Twitter had the most (177,543), followed by Facebook (149,388), Instagram (81,739), and LinkedIn (77,459). We found a significant correlation between the number of social media followers and journal impact factor (Pearson correlation coefficient [PCC] = 0.67; P = 0.003). When analyzing each social media platform independently, we found a significant correlation between the number of Facebook and Twitter followers and journal impact factor (PCC = 0.54; P = 0.02 and PCC = 0.80; P < 0.001, respectively). DISCUSSION: We have shown a notable association between the number of social media followers and a journal's impact factor. With the increasing shift toward online distribution, orthopaedic journals may use our data when evaluating their social media strategy to maintain and potentially increase their exposure and potentially their impact factor.

Teaching during a pandemic: Using high-impact writing assignments to balance rigor, engagement, flexibility, and workload.

The COVID-19 pandemic has created new challenges for instructors who seek high-impact educational practices that can be facilitated online without creating excessive burdens with technology, grading, or enforcement of honor codes. These practices must also account for the possibility that some students may need to join courses asynchronously and have limited or unreliable connectivity. Of the American Association of Colleges and University's list of 11 high-impact educational practices, writing-intensive courses may be the easiest for science faculty to adopt during these difficult times. Not only can writing assignments promote conceptual learning, they can also deepen student engagement with the subject matter and with each other. Furthermore, writing assignments can be incredibly flexible in terms of how they are implemented online and can be designed to reduce the possibility of cheating and plagiarism. To accelerate the adoption of writing pedagogies, we summarize evidence-based characteristics of effective writing assignments and offer a sample writing assignment from an introductory ecology course. We then suggest five strategies to help instructors manage their workload. Although the details of the sample assignment may be particular to our course, this framework is general enough to be adapted to most science courses, including those taught in-person, those taught online, and those that must be able to switch quickly between the two.

Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications.

Cord blood (CB) mononuclear cells (MNC) are being tested in clinical trials to treat hypoxic-ischemic (HI) brain injuries. Although early results are encouraging, mechanisms underlying potential clinical benefits are not well understood. To explore these mechanisms further, we exposed mouse brain organotypic slice cultures to oxygen and glucose deprivation (OGD) and then treated the brain slices with cells from CB or adult peripheral blood (PB). We found that CB-MNCs protect neurons from OGD-induced death and reduced both microglial and astrocyte activation. PB-MNC failed to affect either outcome. The protective activities were largely mediated by factors secreted by CB-MNC, as direct cell-to-cell contact between the injured brain slices and CB cells was not essential. To determine if a specific subpopulation of CB-MNC are responsible for these protective activities, we depleted CB-MNC of various cell types and found that only removal of CB CD14+ monocytes abolished neuroprotection. We also used positively selected subpopulations of CB-MNC and PB-MNC in this assay and demonstrated that purified CB-CD14+ cells, but not CB-PB CD14+ cells, efficiently protected neuronal cells from death and reduced glial activation following OGD. Gene expression microarray analysis demonstrated that compared to PB-CD14+ monocytes, CB-CD14+ monocytes over-expressed several secreted proteins with potential to protect neurons. Differential expression of five candidate effector molecules, chitinase 3-like protein-1, inhibin-A, interleukin-10, matrix metalloproteinase-9 and thrombospondin-1, were confirmed by western blotting, and immunofluorescence. These findings suggest that CD14+ monocytes are a critical cell-type when treating HI with CB-MNC.