Buffering Mitigates Chondrocyte Oxidative Stress, Metabolic Dysfunction, and Death Induced by Normal Saline: Formulation of a Novel Arthroscopic Irrigant.

For decades, surgeons have utilized 0.9% normal saline (NS) for joint irrigation to improve visualization during arthroscopic procedures. This continues despite mounting evidence that NS exposure impairs chondrocyte metabolism and compromises articular cartilage function. We hypothesized that chondrocyte oxidative stress induced by low pH is the dominant factor driving NS toxicity, and that buffering NS to increase its pH would mitigate these effects. Effects on chondrocyte viability, reactive oxygen species (ROS) production, and overall metabolic function were assessed. Even brief exposure to NS caused cell death, ROS overproduction, and disruption of glycolysis, pentose phosphate, and tricarboxylic acid (TCA) cycle pathways. NS also stimulated ROS overproduction in synovial cells that could adversely alter the synovial function and subsequently the entire joint health. Buffering NS with 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) significantly increased chondrocyte viability, reduced ROS production, and returned metabolite levels to near control levels while also reducing ROS production in synovial cells. These results confirm that chondrocytes and synoviocytes are vulnerable to insult from the acidic pH of NS and demonstrate that adding a buffering agent to NS averts many of its most harmful effects.

Long-Term Clinical and Radiographic Follow-Up of Preaxial Polydactyly Reconstruction.

PURPOSE: The purpose of the study was to determine the long-term results of preaxial polydactyly reconstruction through evaluating strength, range of motion, pain, arthritis, and functional outcomes. METHODS: Patients having preaxial polydactyly reconstruction 15 to 60 years ago completed the Disabilities of the Arm, Shoulder, and Hand (DASH) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity (UE) Computer Adaptive Test (CAT). Aggregate scores were compared with those of the general population. Patients completed a clinical evaluation comprising grip strength, pinch strength, side pinch strength, and range of motion. Mean strength and range of motion were compared with the contralateral extremity. Patients had radiographs of the reconstructed thumb to evaluate for arthritis. RESULTS: Twenty-five patients, comprising 27 surgical reconstructions, completed patient-reported outcomes questionnaires, and 13 reconstructions underwent clinical and radiographic evaluation. The median follow-up was 36 years. The most common Flatt-Wassel classification was type IV. The mean DASH score was 3.7, similar to the general population mean of 10.1 (SD, 14.5). The mean PROMIS UE CAT score was 51.5, similar to the general population mean of 50 (SD, 10.0). The mean pinch strength, side pinch strength, and grip strength did not differ significantly from the contralateral extremity. There was significantly decreased range of motion at the interphalangeal joint. No patient had pain in the thumb or hand on clinical evaluation. A minority of patients developed radiographic evidence of interphalangeal joint arthritis (15.4%). Nearly half of patients, 46.2%, had angular deformity. CONCLUSIONS: Preaxial polydactyly reconstruction patients have functional outcomes similar to the general population, despite decreased range of motion at the interphalangeal joint. Patients have maintained pinch strength, side pinch strength, and grip strength. Radiographic findings of arthritis were seen in 15% of patients at follow-up but none of these patients had associated pain. Late angular deformity developed in nearly half of patients, and this highlights the importance of close follow-up until skeletal maturity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

DAMPs Synergize with Cytokines or Fibronectin Fragment on Inducing Chondrolysis but Lose Effect When Acting Alone.

OBJECTIVE AND DESIGN: To investigate whether endogenous damage-associated molecular patterns (DAMPs) or alarmins originated from mitochondria or nucleus stimulates inflammatory response in articular chondrocytes to cause chondrolysis which leads to cartilage degradation featured in posttraumatic osteoarthritis (PTOA). MATERIALS: Primary cultures of bovine or human chondrocytes isolated from cartilage of weight-bearing joints. TREATMENT: Chondrocytes were subjected to mitochondrial DAMPs (MTDs) or HMGB1, a nuclear DAMP (NuD), with or without the presence of an N-terminal 29 kDa fibronectin fragment (Fn-f) or proinflammatory cytokines (IL-1ß and TNF-α). Injured cartilage-conditioned culturing medium containing a mixture of DAMPs was employed as a control. After 24 hrs, the protein expression of cartilage degrading metalloproteinases and iNOS in culture medium or cell lysates was examined with Western blotting, respectively. RESULTS: HMGB1 was synergized with IL-1ß in upregulating expression of MMP-3, MMP-13, ADAMTS-5, ADAM-8, and iNOS. Moreover, a moderate synergistic effect was detected between HMGB1 and Fn-f or between MTDs and TNF-α on MMP-3 expression. However, when acting alone, MTDs or HMGB1 did not upregulate cartilage degrading enzymes or iNOS. CONCLUSION: MTDs or HMGB1 could only stimulate inflammatory response in chondrocytes with the presence of cytokines or Fn-f.

Estimated cause-specific survival continues to improve over time in patients with chondrosarcoma.

BACKGROUND: Conditional survival measures change in the risk of mortality given that a patient has survived a defined period of time. This has yet to be reported for chondrosarcoma of bone. This information should be of interest to the clinician and helpful in counseling patients with chondrosarcoma. QUESTIONS/PURPOSES: Our questions include the following: (1) Does the conditional survival of patients with local/regional chondrosarcoma improve with each additional year of survival? (2) Does the conditional survival of patients with metastatic chondrosarcoma improve with each additional year of survival? (3) Does tumor location, use of radiation, or patient age affect conditional survival? (4) Can chondrosarcoma ever be considered cured? METHODS: We used the Surveillance, Epidemiology, and End Results Program database maintained by the National Cancer Institute to identify 2138 patients with chondrosarcoma of bone from 1973 to 2009. We used an actuarial life table analysis to explore differences in 5-year cause-specific survival estimates conditional on 1 to 5 years of survival. The cohort was stratified by grade, location (axial versus extremity), use of radiation, and age. Finally, we expanded the analysis to include survival estimates 20 years after diagnosis conditional on survival for 5 and 10 years. RESULTS: The estimated survival for all grades of local/regional chondrosarcoma improved from baseline with each year of survival after diagnosis. At 5 years after diagnosis, local/regional Grade 1 chondrosarcoma displayed higher conditional survival than Grade 2 and 3 local/regional chondrosarcoma (97.2% [95% confidence interval {CI}, 95.2%-98.4%] versus 92.8% [95% CI, 89.5%-95.0%], p = 0.006 and 83.8% [95% CI, 69.9%-91.7%], p = 0.012). Estimated survival improved from baseline with each year of survival for all grades of metastatic chondrosarcoma. Conditional survival estimates for Grade 3 axial tumors failed to improve from baseline to 5 years after diagnosis (52.9% versus 70.2%, p > 0.05) compared with Grade 3 extremity tumors at baseline and 5 years after diagnosis (58.1% versus 95.8%, p < 0.0001) The 20-year conditional survival estimates reveal that a cancer-specific risk of mortality exists even 10 years after diagnosis, suggesting that although the conditional survival increases considerably over time, it cannot be considered cured. CONCLUSIONS: The 5-year conditional survival estimate for patients with chondrosarcoma improved with each additional year of survival regardless of grade, site, age, or use of radiation. At 10 years after diagnosis, deaths attributable to cancer were still present, and patients should be aware of this small long-term risk. LEVEL OF EVIDENCE: Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Periostin Is a Biomarker for Anterior Shoulder Instability: Proteomic Analysis of Synovial Fluid.

BACKGROUND: The incremental biological changes in the synovial microenvironment of the shoulder in acute and chronic instability that may contribute to joint degeneration are poorly understood. Proteomic analysis of synovial fluid in patients with shoulder instability may improve our understanding of proteins that are shed into shoulder synovial fluid after an injury. HYPOTHESIS: Injury-specific factors such as the direction of instability and the severity of glenoid and humeral bone loss are associated with the proteome of synovial fluid in patients with shoulder instability. STUDY DESIGN: Descriptive laboratory study. METHODS: Synovial fluid lavage samples were compared between patients with anterior (n = 12) and posterior (n = 8) instability and those without instability (n = 5). Synovial proteins were identified with liquid chromatography-tandem mass spectrometry. Orthogonal validation of protein targets found to be significant on tandem mass spectrometry was performed in a separate set of prospective patients with Western blotting. Data were processed and analyzed, and P values were adjusted with the Benjamini-Hochberg method for multiple comparisons. RESULTS: A total of 25 patients were included. Tandem mass spectrometry identified 720 protein groups in synovial fluid of patients with shoulder instability. There were 4 synovial proteins that were significantly expressed in patients with anterior instability relative to posterior instability: periostin (POSTN) (adjusted P value = .03; log fold change [logFc] = 4.7), transforming growth factor beta-induced protein ig-h3 (adjusted P value = .05; logFc = 1.7), collagen type VI alpha-3 chain (adjusted P value = .04; logFc = 2.6), and coagulation factor V (adjusted P value = .04; logFc = -3.3). Among these targets, POSTN showed a moderate correlation with the Hill-Sachs lesion size (r = 0.7). Prospective validation with Western blotting confirmed a significantly higher level of POSTN in synovial fluid of patients with anterior instability (P = .00025; logFc = 5.1). CONCLUSION: Proteomic analysis enriched our understanding of proteins that were secreted into shoulder synovial fluid of patients with shoulder instability. The identification of POSTN, a proinflammatory catabolic protein involved with tissue remodeling and repair, as a significant target in anterior shoulder instability is a novel finding. Therefore, further study is warranted to determine the role that POSTN may play in the progression of bone loss and posttraumatic osteoarthritis. CLINICAL RELEVANCE: Proteomic analysis of synovial fluid in patients with shoulder instability improved our understanding of this abnormality after an injury.

Chondrogenic progenitor cells respond to cartilage injury.

OBJECTIVE: Hypocellularity resulting from chondrocyte death in the aftermath of mechanical injury is thought to contribute to posttraumatic osteoarthritis. However, we observed that nonviable areas in cartilage injured by blunt impact were repopulated within 7-14 days by cells that appeared to migrate from the surrounding matrix. The aim of this study was to assess our hypothesis that the migrating cell population included chondrogenic progenitor cells that were drawn to injured cartilage by alarmins. METHODS: Osteochondral explants obtained from mature cattle were injured by blunt impact or scratching, resulting in localized chondrocyte death. Injured sites were serially imaged by confocal microscopy, and migrating cells were evaluated for chondrogenic progenitor characteristics. Chemotaxis assays were used to measure the responses to chemokines, injury-conditioned medium, dead cell debris, and high mobility group box chromosomal protein 1 (HMGB-1). RESULTS: Migrating cells were highly clonogenic and multipotent and expressed markers associated with chondrogenic progenitor cells. Compared with chondrocytes, these cells overexpressed genes involved in proliferation and migration and underexpressed cartilage matrix genes. They were more active than chondrocytes in chemotaxis assays and responded to cell lysates, conditioned medium, and HMGB-1. Glycyrrhizin, a chelator of HMGB-1 and a blocking antibody to receptor for advanced glycation end products (RAGE), inhibited responses to cell debris and conditioned medium and reduced the numbers of migrating cells on injured explants. CONCLUSION: Injuries that caused chondrocyte death stimulated the emergence and homing of chondrogenic progenitor cells, in part via HMGB-1 release and RAGE-mediated chemotaxis. Their repopulation of the matrix could promote the repair of chondral damage that might otherwise contribute to progressive cartilage loss.

Conditional survival is greater than overall survival at diagnosis in patients with osteosarcoma and Ewing's sarcoma.

BACKGROUND: Conditional survival is a measure of the risk of mortality given that a patient has survived a defined period of time. These estimates are clinically helpful, but have not been reported previously for osteosarcoma or Ewing's sarcoma. QUESTIONS/PURPOSES: We determined the conditional survival of patients with osteosarcoma and Ewing's sarcoma given survival of 1 or more years. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) Program database to investigate cases of osteosarcoma and Ewing's sarcoma in patients younger than 40 years from 1973 to 2009. The SEER Program is managed by the National Cancer Institute and provides survival data gathered from population-based cancer registries. We used an actuarial life table analysis to determine any cancer cause-specific 5-year survival estimates conditional on 1 to 5 years of survival after diagnosis. We performed a similar analysis to determine 20-year survival from the time of diagnosis. RESULTS: The estimated 5-year survival improved each year after diagnosis. For local/regional osteosarcoma, the 5-year survival improved from 74.8% at baseline to 91.4% at 5 years-meaning that if a patient with localized osteosarcoma lives for 5 years, the chance of living for another 5 years is 91.4%. Similarly, the 5-year survivals for local/regional Ewing's sarcoma improved from 72.9% at baseline to 92.5% at 5 years, for metastatic osteosarcoma 35.5% at baseline to 85.4% at 5 years, and for metastatic Ewing's sarcoma 31.7% at baseline to 83.6% at 5 years. The likelihood of 20-year cause-specific survival from the time of diagnosis in osteosarcoma and Ewing's sarcoma was almost 90% or greater after 10 years of survival, suggesting that while most patients will remain disease-free indefinitely, some experience cancer-related complications years after presumed eradication. CONCLUSIONS: The 5-year survival estimates of osteosarcoma and Ewing's sarcoma improve with each additional year of patient survival. Knowledge of a changing risk profile is useful in counseling patients with time. The presence of cause-specific mortality decades after treatment supports lifelong monitoring in this population. LEVEL OF EVIDENCE: Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes.

We report a mouse model of multiple osteochondromas (MO), an autosomal dominant disease in humans, also known as multiple hereditary exostoses (MHE or HME) and characterized by the formation of cartilage-capped osseous growths projecting from the metaphyses of endochondral bones. The pathogenesis of these osteochondromas has remained unclear. Mice heterozygous for Ext1 or Ext2, modeling the human genotypes that cause MO, occasionally develop solitary osteochondroma-like structures on ribs [Lin et al. (2000) Dev Biol 224(2):299-311; Stickens et al. (2005) Development 132(22):5055-5068]. Rather than model the germ-line genotype, we modeled the chimeric tissue genotype of somatic loss of heterozygosity (LOH), by conditionally inactivating Ext1 via head-to-head loxP sites and temporally controlled Cre-recombinase in chondrocytes. These mice faithfully recapitulate the human phenotype of multiple metaphyseal osteochondromas. We also confirm homozygous disruption of Ext1 in osteochondroma chondrocytes and their origin in proliferating physeal chondrocytes. These results explain prior modeling failures with the necessity for somatic LOH in a developmentally regulated cell type.

Ulnar Variance in Athletes: A Scoping Review.

CONTEXT: Ulnar variance (UV) is a measurement of the relative locations of the radius and ulna that may become perturbed in athletic populations. Positive UV can be associated with wrist pathologies often treated conservatively or surgically and may result in interruption of sports participation. OBJECTIVE: This scoping review aims to summarize diagnostic measures of UV in athletes, describe its relation to separate wrist conditions, and present treatment strategies for symptomatic UV. DATA SOURCES: A systematic search was created and modified for PubMed, CINAHL, Embase, and SPORTDiscus including articles from inception until February 2, 2022. STUDY SELECTION: Articles including UV characterization, imaging modality style, and an athletic population were searched across multiple databases. STUDY DESIGN: A scoping review was designed to identify the methods for imaging UV in athletic populations following the PRISMA Extension for Scoping Reviews (PRISMA-ScR). LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: The specific athletic population, imaging modality, measurement style, wrist pathology association, and surgical management of UV were extracted. RESULTS: A total of 4321 records were screened independently for eligibility: 22 met inclusion criteria. Eight sports comprised the analysis. All studies referenced conventional radiography to diagnose UV; 50% specified the posteroanterior, 18.2% anteroposterior, and 13.6% pronated, gripping radiographs. Hafner's method (7×), Palmer's technique (2×), and the method of perpendiculars (3×) were used to measure UV. Athletes displayed more positive UV than nonathletes and UV became more positive over time in longitudinal studies. Triangular fibrocartilage complex tears, focal lunate necrosis, and ulnar abutment were associated with positive UV. Ulnar shortening osteotomy was the most performed operation for positive UV. CONCLUSION: Conventional radiography is the gold standard for imaging UV in athletes. Hafner's method is the most commonly used radiograph measurement technique. Wrist pathology in athletic populations may indicate positive UV in need for operative management.

Early Versus Delayed Surgery for Midshaft Clavicle Fractures: A Systematic Review.

Background: Orthopaedic surgeons debate the timing of and necessity for surgical intervention when treating displaced midshaft clavicle fractures (MCFs). This systematic review evaluates the available literature regarding functional outcomes, complication rates, nonunion, and reoperation rates between patients undergoing early versus delayed surgical management of MCFs. Methods: Search strategies were applied in PubMed (Medline), CINAHL (EBSCO), Embase (Elsevier), Sport Discus (EBSCO), and Cochrane Central Register of Controlled Trials (Wiley). Following an initial screening and full-text review, demographic and study outcome data was extracted for comparison between the early fixation and delayed fixation studies. Results: Twenty-one studies were identified for inclusion. This resulted in 1158 patients in the early group and 44 in the delayed. Demographics were similar between groups except for a higher percentage of males in the early group (81.6% vs. 61.4%) and longer time to surgery in the delayed group (4.6 days vs. 14.5 months). Disability of the arm, shoulder, and hand scores (3.6 vs. 13.0) and Constant-Murley scores (94.0 vs. 86.0) were better in the early group. Percentages of initial surgeries resulting in complication (33.8% vs. 63.6%), nonunion (1.2% vs. 11.4%), and nonroutine reoperation (15.8% vs. 34.1%) were higher in the delayed group. Conclusion: Outcomes of nonunion, reoperation, complications, DASH scores, and CM scores favor early surgery over delayed surgery for MCFs. However, given the small cohort of delayed patients who still achieved moderate outcomes, we recommend a shared decision-making style for treatment recommendations regarding individual patients with MCFs. Level of Evidence: II.

Posttraumatic osteoarthritis caused by battlefield injuries: the primary source of disability in warriors.

The Army Physical Evaluation Board results for wounded warriors from a previously described cohort were reviewed to identify permanently disabling conditions and whether the conditions were preexisting or caused by battlefield injury. Arthritis was the most common unfitting condition in this cohort, with 94.4% of cases attributed to combat injury and only 5.6% attributed to preexisting conditions or documented in the health records prior to battle injury. The most common causes of injury that resulted in arthritis were intra-articular fractures secondary to explosions, traumatic arthrotomies resulting from fragment projectiles, and gunshot wounds. Arthritis was recognized as a disabling condition an average of 19 ± 10 months after injury. Research is needed to enhance prevention and management of joint injuries in order to minimize the disabling effects of joint degeneration in this young patient population.

Prereferral MRI use in patients with musculoskeletal tumors is not excessive.

BACKGROUND: Inappropriate MRI use has been targeted as a particular area of concern in orthopaedics, but it is unclear whether and to what extent its use is inappropriate in musculoskeletal oncology. QUESTIONS/PURPOSES: We therefore evaluated the incidence and cost of inappropriate prereferral MRI among patients with musculoskeletal tumors. METHODS: We retrospectively identified 920 patients treated in a musculoskeletal oncology clinic between 2009 and 2010. We accepted as necessary any MRI for a primary bone sarcoma, for biopsy-proven soft tissue sarcomas, for soft tissue masses greater than 5 cm in diameter, for soft tissue masses deep to the fascia, for painful soft tissue masses, and for growing soft tissue masses. Patients without these criteria were reviewed by a team of musculoskeletal oncologists to determine the necessity. The criteria for a repeat MRI were failure to show the tumor, lack of gadolinium contrast, lack of T1 or T2 MRI sequence, or poor image quality. Cost was determined using 2010 Medicare reimbursement rates. RESULTS: Of 920 patients, 320 (35%) arrived with a prereferral MRI study. Eight of the 320 (3%) studies were unnecessary, and 12 (4%) were necessary but were repeated. The cost was $11,474, which averages to $574 per study and $36 of waste per patient referred with an MRI study. CONCLUSIONS: Based on our data, we judged MRI use before referral to our tertiary center as not excessive. This is likely attributable, in part, to the relatively low use of MRI in our referral base. Inappropriate MRI use in patients with tumors may not be as widespread as previously reported. LEVEL OF EVIDENCE: Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence.

Efficiency Benefits of Live Fluoroscopy in Hand Clinics.

Background: Postoperative imaging protocols for common hand procedures typically consist of 2-3 plain radiographs at defined intervals dependent on the surgery. Radiographs typically verify reduction, hardware position, and/or evaluate for complications, but also generate costs and alterations in clinic flow. We hypothesize the use of mini-fluoroscopic images will provide comparable clinical data with less cost and improved clinic flow. The objectives of the study were to determine if clinic-based fluoroscopic imaging is feasible for post-operative hand patients and if fluoroscopic imaging results in improved clinic flow (less waiting and more time with provider) and theoretical cost savings using mini-fluoroscopy instead of traditional radiographs. Methods: With institutional review board exemption, the prospective use of mini-fluoroscopic evaluation of post-operative hand surgery patients was compared to traditional radiographs using time-based cohort analysis. Patients who underwent percutaneous pinning of phalanges/metacarpals, ORIF (open reduction and internal fixation) of phalanges/metacarpals or ORIF of distal radius fractures were included to evaluate common hand surgery patients. Each cohort consisted of a 3-month data collection period with prospective measures of clinic flow (wait times, appointment times, time with provider) and estimated cost compared between the groups. Results: 24 patients met inclusion criteria for data analysis; 11 patients in the mini-fluoroscopy group and 13 patients in the traditional radiograph group. Appointments using mini-fluoroscopy were 24 minutes shorter (53 vs 77 minutes) from patient check-in to check out time. Check-in time to rooming was 10 minutes quicker (9 vs. 19 minutes) using mini-fluoroscopy. Traditional hand radiographs have a face-value of $734 per appointment/series for a total theoretical savings of $9540 (n=13). Conclusion: The use of mini-fluoroscopy during orthopedic hand surgery post-operative visits provides a feasible, quick, cost effective way to evaluate patients postoperatively, ultimately, resulting in quicker patient appointments and greater time spent with providers. Level of Evidence: III.

Menstrual hormone-induced cyclic thumb CMC instability and degeneration in women: a systematic review.

BACKGROUND: Relaxin is a hormone which peaks during the luteal phase of the menstrual cycle, and a known collagenolytic promoter that has been shown to avidly bind tissues supporting the trapeziometacarpal (TMC) joint in women. We hypothesize a causal linkage between cyclic binding of relaxin to the supporting tissues of the female TMC joint; and to the earlier onset of more severe TMC osteoarthritis (OA) commonly seen in women. METHODS: A systematic literature review was performed per PRISMA guidelines, qualitatively and quantitatively assessing papers regarding relaxin-TMC joint stability interactions. The primary outcome variable was TMC joint degeneration/loss of function; the "late stage" consequences of relaxin-induced instability. The secondary outcome variable was presence of early signs of relaxin-induced instability; specifically asymptomatic TMC joint laxity in young women. RESULTS: In healthy young women, menstrual cycle relaxin peaks corresponded with asymptomatic TMC joint instability. Immunohistochemical studies of TMC arthroplasty patients showed avidly increased relaxin binding to supporting tissues around the TMC joint in women but not men. Demographic analysis of patients from the TMC arthroplasty studies show a predominantly female cohort, who were on average significantly younger than the male surgical patients. CONCLUSIONS: Each relaxin peak during the menstrual cycle can target receptors on the soft tissues supporting the TMC joint, including-critically-the main stabilizing ligament: the anterior oblique. The cyclic instability is typically asymptomatic for years after menarche, but causes cumulative chondral microtrauma. This likely causes the early-onset, high severity TMC joint OA clinically pervasive among female patients at orthopedic hand clinics. Further research is indicated to develop risk assessment strategies and potential interventional options before and after the onset of hormonal laxity-induced OA.

The Rurality of Lower Extremity Firearm Injuries.

Background: To highlight the unique spectrum of lower extremity firearm injuries seen at a rural, Midwestern level 1 trauma center to provide insight into prevalence, mechanism of injury, and identify modifiable factors that contribute to firearm injuries of the lower extremity. It is our belief that the creation of our database will help future trauma and firearm databases improve documentation and understand the relationship between anatomic location of injury and outcomes. Methods: A retrospective review of lower extremity firearm injuries from a rural, Midwestern level 1 trauma center was collected from January 2011 to December 2019. Data acquired included injury description; demographics, injury mechanism/ description/ location, firearm used, toxicology, and information regarding hospitalization. Data was analyzed using Chi-squared analysis and Fisher's exact test for categorical data and the Wilcoxon rank sum test for continuous data. Results: 69 patients with lower extremity firearm injuries were identified. Average age was 30.14 years, 89.86% were males, and one fatality were identified. 47.83% (33) of these injuries were assaults, followed by unintentional injuries at 42.03% (29). Law enforcement-related and self-inflicted injuries contributed minimally. Handguns were the most common type of firearm, used in 72.5% of cases. Nearly 1/3 of the unintentional firearm injuries occurred during November or December, the active deer hunting months in the community of study. Conclusion: The lower extremity is uniquely vulnerable to both assaults and unintentional injury in our rural environment, differing from what we have previously published regarding the upper extremity. Lower extremity gunshot wounds increased during the winter months, offering a correlation to deer hunting season. Our findings display that not all firearm injuries are created equal, and that there is a need to improve documentation of and additional study in order to optimally tailor firearm prevention measures based on the ruralityurbanicity spectrum. Level of Evidence: III.

Objective evaluation of chondrocyte density & cloning after joint injury using convolutional neural networks.

Variations in chondrocyte density and organization in cartilage histology sections are associated with osteoarthritis progression. Rapid, accurate quantification of these two features can facilitate the evaluation of cartilage health and advance the understanding of their significance. The goal of this work was to adapt deep-learning-based methods to detect articular chondrocytes and chondrocyte clones from safranin-O-stained cartilage to evaluate chondrocyte cellularity and organization. The U-net and "you-only-look-once" (YOLO) models were trained and validated for identifying chondrocytes and chondrocyte clones, respectively. Validated models were then used to quantify chondrocyte and clone density in talar cartilage from Yucatan minipigs sacrificed 1 week, 3, 6, and 12 months after fixation of an intra-articular fracture of the hock joint. There was excellent/good agreement between expert researchers and the developed models in identifying chondrocytes/clones (U-net: R2 = 0.93, y = 0.90x-0.69; median F1 score: 0.87/YOLO: R2 = 0.79, y = 0.95x; median F1 score: 0.67). Average chondrocyte density increased 1 week after fracture (from 774 to 856 cells/mm2 ), decreased substantially 3 months after fracture (610 cells/mm2 ), and slowly increased 6 and 12 months after fracture (638 and 683 cells/mm2 , respectively). Average detected clone density 3, 6, and 12 months after fracture (11, 11, 9 clones/mm2 ) was higher than the 4-5 clones/mm2 detected in normal tissue or 1 week after fracture and show local increases in clone density that varied across the joint surface with time. The accurate evaluation of cartilage cellularity and organization provided by this deep learning approach will increase objectivity of cartilage injury and regeneration assessments.

Mapping early brain development in autism.

Although the neurobiology of autism has been studied for more than two decades, the majority of these studies have examined brain structure 10, 20, or more years after the onset of clinical symptoms. The pathological biology that causes autism remains unknown, but its signature is likely to be most evident during the first years of life when clinical symptoms are emerging. This review highlights neurobiological findings during the first years of life and emphasizes early brain overgrowth as a key factor in the pathobiology of autism. We speculate that excess neuron numbers may be one possible cause of early brain overgrowth and produce defects in neural patterning and wiring, with exuberant local and short-distance cortical interactions impeding the function of large-scale, long-distance interactions between brain regions. Because large-scale networks underlie socio-emotional and communication functions, such alterations in brain architecture could relate to the early clinical manifestations of autism. As such, autism may additionally provide unique insight into genetic and developmental processes that shape early neural wiring patterns and make possible higher-order social, emotional, and communication functions.

The Rurality of Upper Extremity Firearm Injuries.

BACKGROUND: To highlight the unique spectrum of hand and upper extremity firearm injuries seen at a rural, Midwestern level 1 trauma center and identify modifiable factors that contribute to firearm injuries of the hand and upper extremity. METHODS: A retrospective review of upper extremity firearm injuries from a rural, Midwestern level 1 trauma center was collected from January 2002 to December 2019. Data acquired included injury description, demographics, injury mechanism/description/location, firearm used, toxicology, and information regarding hospitalization. Data was analyzed using Chi-squared analysis and Fisher's exact test for categorical data and the Wilcoxon rank sum test for continuous data. RESULTS: 55 patients with upper extremity firearm injuries were identified. Average age was 33.3 ± 13.0 years, 81.8% were males, and zero fatalities were identified. 58% (38) of these injuries were unintentional firearm injuries, followed by assaults at 34.6% (19). Law enforcement-related and self-inflicted injuries contributed minimally. Handguns were the most common type of firearm, used in 43.6% of cases. 7.3% (4) of injuries occurred while hunting, with 21.8% (12) total during November or December, the active deer hunting months. 92.7% (51) of all firearm injuries presented with fracture, among which 92.2% (47) met a Gustilo-Anderson classification score of at least 3A. Alcohol was detected in 20% (11) of the patients, while other drugs of abuse were detected in 36.4% (20). CONCLUSION: Our data suggests that upper extremity firearm injuries in a rural population are unique from urban injuries in that they are predominately unintentional, isolated, and non-fatal. We identify a distinct rural cohort that may benefit from better directed interventions to prevent firearm injuries and ultimately guide firearm education and public policy.Level of Evidence: III.

Migrating Progenitor Cells Derived From Injured Cartilage Surface Respond to Damage-Associated Molecular Patterns.

OBJECTIVE: To delineate the response of migrating chondrogenic progenitor cells (CPCs) that arose from the surface of mechanically injured articular cartilage to proinflammatory damage-associated-molecular-patterns (DAMPs). DESIGN: Bovine CPCs and non-CPC chondrocytes isolated from either impacted or scratched articular cartilage were studied. Those 2 types of cells were treated with mitochondrial DAMPs (MTDs; 10 nM fMLF and 10 µg/mL CpG DNA), or 10 nM HMGB1, or 10 ng/mL IL-1b for 24 hours. At the end of experiments, conditioned media and cell lysates were collected for analysis of expression levels of matrix metalloproteinases (MMPs), chemokines, and cytokines that are associated with cartilage degeneration with Western blotting and quantitative polymerase chain reaction. The difference of expression levels was compared by Welch's t-test. RESULTS: Our data indicated that HMGB1 and MTDs remarkably upregulated pro-MMP-13 expression in CPCs. Compared with non-CPCs, CPCs expressed significantly more baseline mRNAs of MMP-13, CXCL12, and IL-6. MTDs greatly increased the expression of MMP-13 and IL-6 in CPCs by over 100-fold (P < 0.001). MTDs also significantly increased IL-8 expression in CPCs to a similar extent (P < 0.001). However, when IL-1b was present, CPCs expressed less MMP-3 and active MMP-13 proteins as well as less CCL2 and IL-6 than did non-CPCs. CONCLUSIONS: We concluded that CPCs were more sensitive than non-CPCs in response to DAMPs, especially MTDs. The proinflammatory nature of CPCs implied their critical role in the early phase of posttraumatic osteoarthritis development.

Inclusion of Olecranon Osteotomy With the Posterior Approach for Fixation of Distal Humerus Fractures (OTA/AO 13) Does Not Increase Surgical Complications.

OBJECTIVES: To determine if inclusion of an olecranon osteotomy to the posterior paratricipital approach for operative fixation of distal humerus fractures significantly affects surgical complication rates (OTA/AO 13). DESIGN: Retrospective comparative cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Three hundred four patients underwent open reduction internal fixation of a distal humerus fracture between 2007 and 2017. Of those, 134 met inclusion criteria (≥15 years, OTA/AO fracture type 13A, B, or C, and posterior surgical approach) for the study (n = 64 with olecranon osteotomy; n = 70 without olecranon osteotomy). INTERVENTION: Open reduction internal fixation of distal humerus fractures performed using a posterior paratricipital approach with or without olecranon osteotomy. MAIN OUTCOME MEASURE: Ulnar neuropathy (UN), fracture site bony nonunion, and surgical site infection (SSI). RESULTS: Thirty-one (33.3%) who underwent the paratricipital approach without olecranon osteotomy, and 15 patients (26.8%) who underwent olecranon osteotomy reported postoperative UN with no significant difference between approaches (P = 0.438). There was no significant difference in rates of SSI (P = 0.418) or fracture site nonunion (P = 0.263) when comparing the approaches. Subjects with Charlson comorbidity index ≥2 were more likely to not undergo an olecranon osteotomy (P = 0.01), whereas subjects with more complex fractures by OTA/AO classification were more likely to have an olecranon osteotomy approach (P = 0.001). CONCLUSIONS: Addition of an olecranon osteotomy with the paratricipital approach for fixation of distal humerus fractures does not result in higher rates of UN, fracture site nonunion, or SSI. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.