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Background: Biomarkers of infection are measurable indicators that reflect the presence of an infection in the body. They are particularly valuable for detecting infections and tracking treatment responses. Previous transcriptome analysis of peripheral blood mononuclear cells (PBMCs) collected from patients during the active phase of diabetic foot infection identified the upregulation of several genes, including a neutrophil-specific cell surface glycoprotein, CD177, an Myb-related transcription factor 2 (MYBL2), and ribonucleotide reductase regulatory subunit M2 (RRM2). We aimed to investigate whether these observations in diabetic foot infections could be extrapolated to other musculoskeletal infections., Questions/purposes: (1) Are the protein concentrations of CD177, MYBL2, and RRM2 elevated in serum or PBMCs of patients with musculoskeletal infections? (2) Do serum and PBMC concentrations of CD177, MYBL2, and RRM2 decrease in response to antibiotic therapy? (3) Can these biomarkers give diagnostic accuracy and differentiate patients with musculoskeletal infections from controls?, Methods: From April 2023 to June 2024, we treated 26 patients presenting with clinical symptoms and signs of acute musculoskeletal infections, including elevated inflammatory markers (white blood cell [WBC] and C-reactive protein [CRP]) and local changes such as swelling, erythema, tenderness or pain, warmth, purulent drainage, sinus tract, or wound leading to bone or hardware. Diagnosis included periprosthetic joint infection (PJI), foot and ankle infection (FAI), fracture-related infection (FRI), and septic arthritis of the native joints. Patients with chronic recurrent osteomyelitis, PJI, or FRI were excluded from the study. Among the 26 patients deemed potentially eligible, 19% (5) were excluded for the following reasons: prison inmate (1), unable to provide consent because of severe sepsis (1), mental illness (1), and declined to participate (2). Of the 81% (21) of patients who provided consent, cultures from 9.5% (2) were negative. These two patients were ultimately diagnosed with inflammatory arthritis: gout (1) and rheumatoid arthritis (1); thus, the musculoskeletal infection group for analysis consisted of 73.1% (19 of 26) of patients. A control group of 21 patients undergoing elective foot or ankle deformity correction surgery without infections or systemic inflammation was included. Because foot or ankle deformity is highly unlikely to influence the immunologic profile of the subjects, we believed that these patients would serve as an appropriate control group. Other than the absence of infection and the lower prevalence of diabetes mellitus, the control group was comparable to the study group in terms of demographics and clinical factors, including age and sex distribution. We collected blood samples from both patients and controls and quantified CD177, MYBL2, and RRM2 RNA transcription levels in the PBMC using qRT-PCR. We also assessed protein concentrations in the serum and PBMC using an enzyme-linked immunosorbent assay. A comparative analysis of the three biomarkers was performed on 19 patients with musculoskeletal infections with positive cultures and 21 controls to assess their diagnostic potential using the unpaired nonparametric t-test with the Mann-Whitney test. We obtained 8-week follow-up blood samples from seven patients with musculoskeletal infections who clinically healed. Healing was defined by normalization of inflammatory markers (WBC and CRP) and absence of swelling, erythema, local tenderness or pain, warmth, purulent drainage, sinus tract, or open wound. We performed a comparative analysis of the seven patients during active infection and after treatment to determine a change in the level of CD177, MYBL2, and RRM2 in their serum and PBMCs. These findings were also compared with those of the control group. We evaluated the diagnostic accuracy of CD177, MYBL2, and RRM2 for musculoskeletal infections using receiver operating characteristic (ROC) curve analysis., Results: The musculoskeletal infections group showed a larger increased serum and PBMC concentrations of CD177, MYBL2, and RRM2 proteins compared with the control group. The mean protein concentrations of CD177, MYBL2, and RRM2 were increased in the serum and PBMC of the musculoskeletal infections group compared with the controls. Serum levels of all biomarkers investigated were higher in musculoskeletal infections group compared with the control group (CD177 227 [155 to 432] versus 54 [10 to 100], difference of medians 173, p < 0.01; MYBL2 255 [231 to 314] versus 180 [148 to 214], difference of medians 75, p < 0.01; RRM2 250 [216 to 305] versus 190 [148 to 255], difference of medians 60, p < 0.01). Similarly, PBMC levels of all biomarkers were higher in the musculoskeletal infections group (CD177 55.3 [39.1 to 80.5] versus 17.5 [10.5 to 27.5], difference of medians 37.8, p < 0.01; MYBL2 144 [114 to 190] versus 91 [70 to 105], difference of medians 53, p < 0.01; RRM2 168 [143 to 202] versus 100 [77.5 to 133], difference of medians 68, p < 0.01). Additionally, serum levels of all biomarkers decreased in seven patients with musculoskeletal infections after infection treatment (CD177 3080 [2690 to 3320] versus 4250 [3100 to 8640], difference of medians 1170, p < 0.01; MYBL2 4340 [4120 to 4750] versus 5010 [4460 to 5880], difference of medians 670, p < 0.01; RRM2 4350 [3980 to 5000] versus 5025 [4430 to 6280], difference of medians 675, p = 0.01). Similarly, PBMC levels of all biomarkers were lower after infection treatment (CD177 805 [680 to 980] versus 1025 [750 to 1610], difference of medians 220, p < 0.01; MYBL2 2300 [2100 to 2550] versus 2680 [2220 to 3400], difference of medians 380, p = 0.02; RRM2 2720 [2500 to 3200] versus 3350 [2825 to 4030], difference of medians 630, p < 0.01). The area under the ROC curve for diagnosing musculoskeletal infections in the serum and PBMC was as follows: CD177 95% confidence interval [CI] > 0.99 and > 0.99, MYBL2 95% CI > 0.99 and > 0.99, and RRM2 95% CI = 0.96 and > 0.99, respectively., Conclusion: We may utilize blood-based tests for CD177, MYBL2, and RRM2 to aid in the diagnosis of musculoskeletal infections, particularly when arthrocentesis or obtaining tissue culture is challenging. They may also assist in monitoring treatment response. As some of these biomarkers may also be elevated in other inflammatory conditions, a large-scale clinical study is needed to confirm their reliability in differentiating musculoskeletal infections from other inflammatory conditions., Clinical Relevance: CD177, MYBL2, and RRM2 proteins in blood samples may serve as novel biomarkers for diagnosing and monitoring treatment response in musculoskeletal infections., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2025 by the Association of Bone and Joint Surgeons.)

The femoral neck system (FNS) was recently introduced for treatment of femoral neck fractures. A novel feature is an anti-rotation screw with a diverging design from the neck bolt to provide rotational stability. Using the 4 Nm torque limiting screwdriver might cause the incomplete insertion of the screw specifically in dense or sclerotic bone. A nontorque limiting manual screwdriver should be used to complete the insertion and locking of the screw to prevent this error. We present series of seven cases with incomplete insertion of the anti-rotation screw in patient with femoral neck fractures treated with the FNS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

As genomic databases expand and artificial intelligence tools advance, there is a growing demand for efficient characterization of large numbers of proteins. To this end, here we describe a generalizable pipeline for high-throughput protein purification using small-scale expression in E. coli and an affordable liquid-handling robot. This low-cost platform enables the purification of 96 proteins in parallel with minimal waste and is scalable for processing hundreds of proteins weekly per user. We demonstrate the performance of this method with the expression and purification of the leading poly(ethylene terephthalate) hydrolases reported in the literature. Replicate experiments demonstrated reproducibility and enzyme purity and yields (up to 400 µg) sufficient for comprehensive analyses of both thermostability and activity, generating a standardized benchmark dataset for comparing these plastic-degrading enzymes. The cost-effectiveness and ease of implementation of this platform render it broadly applicable to diverse protein characterization challenges in the biological sciences., (© 2024. The Author(s).)

A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed to accurately predict combinations of mutations that maintain or enhance function. Models of sequence co-variation (e.g., EVcouplings), which leverage extensive information about various protein properties and activities from homologous protein sequences, have proven effective for many applications including structure determination and mutation effect prediction. We apply EVcouplings to computationally design variants of the model protein TEM-1 β-lactamase. Nearly all the 14 experimentally characterized designs were functional, including one with 84 mutations from the nearest natural homolog. The designs also had large increases in thermostability, increased activity on multiple substrates, and nearly identical structure to the wild type enzyme. This study highlights the efficacy of evolutionary models in guiding large sequence alterations to generate functional diversity for protein design applications., (© 2024. The Author(s).)

Purpose: Ligament reconstruction and tendon interposition is a common technique for thumb basal joint arthroplasty. Recently, a variation of this technique, a suture suspensionplasty, has been introduced. The goal of our study was to assess the optimal position of the bone anchor in the thumb metacarpal. We hypothesized that an anchor placed in the radial aspect of the thumb metacarpal base would provide improved stability and resist subsidence more effectively than an ulnar-based thumb anchor., Methods: Eight fresh-frozen cadaver arms were imaged fluoroscopically in anteroposterior and lateral views centered over the thumb carpometacarpal joint before and after trapeziectomy and after the placement of radial-based and ulnar-based bone anchors. The intermetacarpal angle between the thumb and index metacarpals was measured on all images after the application of a standard force. Radial abduction, opposition, subsidence, palmar abduction, and adduction were measured. Subsidence was calculated as the percentage loss of the trapezial space., Results: Both radially and ulnarly placed internal brace constructs allowed more radial abduction, opposition, and palmar abduction than the pretrapeziectomy constructs. They both also reduced subsidence by approximately 20% to 29% compared with the posttrapeziectomy constructs. Comparing radial to ulnar constructs, motion and subsidence were similar., Conclusions: There was immediate stability of the thumb with respect to axial load and subsidence after anchor placement, and this was independent of the anchor position. The position of the bone anchor in the thumb metacarpal base did not affect the range of motion. Although the device can limit subsidence, it does not appear to restrict any range of motion of the thumb, irrespective of anchor position., Clinical Relevance: This cadaver study can help hand surgeons understand the effect of positioning of bone anchors when performing a specific suture suspensionplasty technique., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Objectives: Finding a first job after fellowship can be stressful due to the uncertainty about which resources to use, including fellowship program directors, residency faculty, and other sources. There are more than 90 orthopaedic trauma fellows seeking jobs annually. We surveyed orthopaedic trauma fellows to determine the job search process., Design: An anonymous 37-question survey., Setting: Online Survey., Patient Selection Criteria: Orthopaedic trauma fellows from the 5 fellowship-cycle years of 2016-2021., Outcome Measures and Comparisons: The primary questions were related to the job search process, current job, and work details. The secondary questions addressed job satisfaction. Data analysis was performed using STATA 17., Results: There were 159 responses (40%). Most of the respondents completed a fellowship at an academic program (84%). Many (50%) took an academic job and 24% were hospital employed. Sixteen percent had a job secured before fellowship and 49% went on 2-3 interviews. Word of mouth was the top resource for finding a job (53%) compared with fellowship program director (46%) and residency faculty (33%). While 82% reported ending up in their first-choice job, 34% of respondents felt they "settled." The number of trauma cases was important (62%), ranked above compensation (52%) as a factor affecting job choice. Surgeons who needed to supplement their practice (46%) did so with primary and revision total joints (37%)., Conclusions: Jobs were most often found by word of mouth. Most fellows landed their first job choice, but still a third of respondents reporting settling on a job. Case volume played a significant role in factors affecting job choice., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Designing optimized proteins is important for a range of practical applications. Protein design is a rapidly developing field that would benefit from approaches that enable many changes in the amino acid primary sequence, rather than a small number of mutations, while maintaining structure and enhancing function. Homologous protein sequences contain extensive information about various protein properties and activities that have emerged over billions of years of evolution. Evolutionary models of sequence co-variation, derived from a set of homologous sequences, have proven effective in a range of applications including structure determination and mutation effect prediction. In this work we apply one of these models (EVcouplings) to computationally design highly divergent variants of the model protein TEM-1 β-lactamase, and characterize these designs experimentally using multiple biochemical and biophysical assays. Nearly all designed variants were functional, including one with 84 mutations from the nearest natural homolog. Surprisingly, all functional designs had large increases in thermostability and most had a broadening of available substrates. These property enhancements occurred while maintaining a nearly identical structure to the wild type enzyme. Collectively, this work demonstrates that evolutionary models of sequence co-variation (1) are able to capture complex epistatic interactions that successfully guide large sequence departures from natural contexts, and (2) can be applied to generate functional diversity useful for many applications in protein design.

Purpose: To expand the current knowledge of tubulointerstitial nephritis and uveitis syndrome (TINU), which might assist other ophthalmologists in recognizing and treating patients with this rare disease., Methods: A patient with atypical demographics and features was compared with previously described TINU cases. The case was analyzed in terms of how it compares with more "classic" cases, and the differences were identified., Results: The diagnosis of TINU is ultimately clinical, although aided by previous studies. Thus, it might present challenges when patients do not have the typical demographics or presenting features of TINU., Conclusions: Our patient showed features that deviated from classic TINU. Knowledge of the disease and a comprehensive view of the patient's medical state might help lead to accurate diagnosis and treatment., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Influenza A virus's (IAV's) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV's genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem-loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA&#95;WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term 'programmable antivirals', with implications for antiviral prophylaxis and post-exposure therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To report diffuse orbital inflammation as a manifestation of recurrent inflammation in a patient with Vogt-Koyanagi-Harada (VKH) disease., Observations: 20-year-old African American male, who was previously diagnosed with VKH, presented with right eye pain, swelling, and binocular double vision. He had run out of methotrexate while on steroid taper. Neuroimaging was consistent with diffuse orbital inflammation with myositis. He was started on intravenous steroids and then transitioned to oral steroids, with complete resolution of his symptoms., Conclusions and Importance: Central nervous system involvement as a manifestation of VKH has been previously reported, however, there have been no reports of orbital inflammatory syndrome resulting from VKH. Thus, in the appropriate clinical context, orbital signs may be recognized as features of recurrent VKH., Competing Interests: The following authors have no financial disclosures: BF, AF, VB, HZ., (© 2022 The Authors. Published by Elsevier Inc.)

Orthopaedic surgeons are among the highest prescribers of opioids. This study explores the effect of an educational intervention on orthopaedic surgery residents' opioid knowledge and prescribing practices. Orthopaedic residents were surveyed at three urban academic institutions. A pre-survey was administered to residents prior to an educational lecture and case-based session. This included background on the opioid epidemic, multimodal analgesia, opioid consumption in common orthopaedic procedures, and state laws regulating prescribing. Following this intervention, residents were given a post-survey to complete. There was a significant increase in resident confidence concerning their opioid prescribing training (p = 0.03) and their knowledge of alternative pain management therapies (p = 0.03). This was accompanied by an objective improvement in knowledge of state prescribing laws and of metrics regarding the opioid epidemic. Hypothetical opioid pills prescribed after common orthopaedic procedures decreased between the pre- and post-tests. The educational session significantly improved orthopaedic surgery residents' knowledge about opioids and prescribing habits. Formal resident education on opioid knowledge and evidence-based prescribing strategies is an area of potential improvement to combat the opioid crisis. (Journal of Surgical Orthopaedic Advances 31(1):030-033, 2022).

Background: Total ankle arthroplasty (TAA) is an increasingly popular option for the operative treatment of ankle arthritis. The Cadence TAA entered clinical use in 2016 and was designed to address common failure modes of prior systems. We report early complications and radiographic and clinical outcomes of this total ankle system at a minimum of 2 years of follow-up., Methods: We performed a retrospective review of a consecutive cohort of patients undergoing primary Cadence TAA by a single surgeon from 2016 to 2017. Complications and reoperations were documented using the American Orthopaedic Foot & Ankle Society (AOFAS) TAA reoperation coding system. Patients completed the Foot and Ankle Ability Measure (FAAM) Activities of Daily Living (ADL) and Sport subscales, SF-12 Mental (MCS) and Physical (PCS) Component Summaries, and visual analog scale (VAS) pain rating (0-100). Radiographic evaluation was performed to assess postoperative range of motion (ROM) of the sole of the foot relative to the long axis of the tibia, alignment, and implant complications., Results: Fifty-eight patients with a mean age of 63.3 years and mean body mass index of 31.9 kg/m 2 were included. Twelve of 58 patients (20.7%) underwent an additional procedure(s) within 2 years, including 3 (5.2%) who required removal of one or both components, 2 for infection and 1 for osteolysis. Forty-three patients were followed for a minimum of 2 years with radiographic imaging; 1 patient's (2.3%) radiographs had signs of peri-implant osteolysis, with no cases demonstrating loosening or subsidence. FAAM-ADL, FAAM-Sport, SF-12 PCS, and VAS pain scores all improved at a mean of 27.4 months postoperatively, with mean score changes (± SD) of 16.3 (± 22.0), 25.3 (± 24.5), 6.0 (± 11.1), and -32.3 (± 39.8), respectively. Radiographic analysis revealed that average coronal alignment improved from 6.9 degrees from neutral preoperatively to 2.3 degrees postoperatively. The average ROM of the foot relative to the tibia was 36.5 degrees total arc of motion based on lateral radiographs., Conclusion: Early experience with this 2-component total ankle replacement was associated with a high component retention rate, improved coronal plane alignment, good postoperative ROM, radiographically stable implants, and improved patient function., Level of Evidence: Level IV, case series.

Introduction: Fracture nonunion remains a devastating complication and may occur for several reasons, though the microbial contribution remains poorly estimated. Next-generation sequencing (NGS) techniques, including 16S rRNA gene profiling, are capable of rapid bacterial detection within clinical specimens. Nonunion cases may harbor microbes that escape detection by conventional culture methods that contribute to persistence. Our aim was to investigate the application of NGS pathogen detection to nonunion diagnosis., Methods: In this prospective multicenter study, samples were collected from 54 patients undergoing open surgical intervention for preexisting long-bone nonunion (n = 37) and control patients undergoing fixation of an acute fracture (n = 17). Intraoperative specimens were sent for dual culture and 16S rRNA gene-based microbial profiling. Patients were followed for evidence of fracture healing, whereas patients not healed at follow-up were considered persistent nonunion. Comparative analyses aimed to determine whether microbial NGS diagnostics could discriminate between nounions that healed during follow-up versus persistent nonunion., Results: Positive NGS detection was significantly correlated with persistent nonunion, positive in 77% more cases than traditional culture. Nonunion cases were observed to have significantly increased diversity and altered bacterial profiles from control cases., Discussion: NGS seems to be a useful adjunct in identification of organisms that may contribute to nonunion. Our findings suggest that the fracture-associated microbiome may be a significant risk factor for persistent nonunion. Ongoing work aims to determine the clinical implications of isolated organisms detected by sequencing and to identify robust microbial predictors of nonunion outcomes., Level of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: J. Parvizi and C. Tipton are consultants for MicroGenDx. J. D. Conway is a consultant for Bonesupport, Orthofix, Smith + Nephew, and Zimmer Biomet; receives fellowship support from Biocomposites; is on the MicroGenDX advisory board; and her spouse receives royalties from the University of Florida. The following organizations supported the institution of J. D. Conway: Biocomposites, DePuy Synthes Companies, MHE Coalition, Orthofix, OrthoPediatrics, Pega Medical, Smith + Nephew, Stryker, and Zimmer Biomet. The remaining authors report no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surgical treatment of basal joint arthritis commonly consists of trapeziectomy followed by various suspensionplasty techniques to provide stability to the thumb ray. Our study goal was to assess the motion and stability of the thumb ray after trapeziectomy and placement of a suture button (Mini TightRope®, Arthrex, Naples, Florida) in a high- or low-angle trajectory. We hypothesized that a low-angle trajectory would yield the greatest stability while providing maximal motion of the thumb. Methods: Eleven fresh-frozen cadaver arms were imaged fluoroscopically in anterior-posterior and lateral views before and after trapeziectomy, and after placement of low- and high-angle suture buttons. The intermetacarpal angle between the thumb and index metacarpals was measured after application of a standard force. Radial abduction, opposition, subsidence, palmar abduction, adduction, and subsidence were measured. Results: Compared to posttrapeziectomy constructs, low- and high-angle TightRope constructs demonstrated less subsidence, low-angle TightRopes had less palmar abduction, and high-angle TightRope constructs had less radial abduction and adduction. High-angle TightRopes allowed more palmar abduction than low-angle constructs. The high-angle TightRopes trended toward more subsidence than low-angle constructs, although it was not significant. Conclusions: Both TightRope constructs provided improved axial stability after trapeziectomy while not excessively limiting any one motion of the thumb. Compared to the high-angle trajectory, the low-angle TightRope placement provided a more stable construct with respect to subsidence and angular motion. Given the concern for excessive motion of the first metacarpal base with the high-angle construct, we recommend a low-angle trajectory TightRope placement.

Introduction: Orthopedic instrumentation is generally made as one-size-fits-all. The purpose of this study was to evaluate the effects of hand size and sex on ease of use and injury rates from orthopedic tools and surgical instruments., Methods: An anonymous 21-item online survey was distributed to orthopedic trainees and attendings. Questions regarding demographics, physical symptoms and treatment, perceptions, and instrument-specific concerns were included. The analysis included statistics comparing responses based on sex, height, and glove size, with significance as p<0.05., Results: There were 204 respondents: 119 female and 84 male. Male and female respondents differed significantly in height (mean difference 5.4 in, p<0.001) and glove size (median size 6.5 size for females, size 8 for males, p<0.001). While 69.8% of respondents reported physical discomfort or symptoms they attributed to their operating instruments, female surgeons were significantly more likely to endorse symptoms (87.3% female vs. 45.2% male, p<0.001). Of those reporting symptoms, 47.7% had undergone treatment, with no significant difference by surgeon sex (p=0.073). Female surgeons were significantly more likely than their male counterparts to have negative attitudes toward orthopedic surgical instruments and to report specific surgical instruments as difficult or uncomfortable to use., Conclusion: Female orthopedic surgeons are more likely than their male counterparts to report physical symptoms attributed to orthopedic surgical instruments, to have negative attitudes toward instruments, and to identify a larger number of common instruments as difficult or uncomfortable to use. Further emphasis on ergonomic instrument design is needed to allow all orthopedic surgeons to operate as safely and effectively as possible., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Fram et al.)

The optimal surgical approach for acute compartment syndrome (ACS) of the lower leg remains debatable. Although a majority of surgeons tend to use a 2-incision approach to 4-compartment fasciotomies, the authors have used a single-incision technique followed by protocolized, staged skin closure. The purpose of this study was to determine the safety, efficacy, and complication rate of this strategy. This retrospective study included all patients treated for ACS by a single surgeon during a 3-year period. A protocol was used including a single-incision technique followed by vacuum-assisted wound-closure dressing, periodic return to the operating room at 48- to 72-hour intervals, and sequential wound closure with vertical mattress sutures. Complications associated with this protocol were analyzed. Eleven patients were included in the study. Average length of follow-up was 12 months (range, 2-35 months). There were no instances of malunion, deep or superficial infection, intraoperative neurovascular injury, or progressive neurologic deficits-indicating adequate release of all 4 compartments through a single incision. All patients were closed primarily without need for skin grafting. Average time to primary closure was 4.5 days. One patient had a tibial fracture nonunion and 1 had distal wound breakdown, which healed by secondary intention. A single-incision approach to 4-compartment fasciotomies followed by protocolized skin closure is safe and effective and may reduce the need for skin grafting. [Orthopedics. 2020;43(4):e225-e230.]., (Copyright 2020, SLACK Incorporated.)

Introduction: Fracture-related infection (FRI) is a common complication associated with orthopaedic fracture care. Diagnosing these complications in the preoperative setting is difficult. Platelets are a known acute phase reactant with indices that change in accordance with infection and inflammation. The purpose of our study was to assess the diagnostic utility of platelet indices at assessing FRI. Methods: A retrospective review performed for all patients who underwent revision surgery for fracture nonunion between 2013 and 2018. Radiographs were employed to define nonunion. Intraoperative cultures were used to define FRI. Receiver operator characteristic (ROC) curve analysis was used to assess the diagnostic ability of preoperative erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and the platelet count/mean platelet volume ratio (P/V) at recognizing FRI. Results: Of the 53 revision surgeries that were performed for fracture nonunion, 17 (32.1%) were identified as FRI. There were no significant demographic differences between the two cohorts. Patients with FRIs exhibited higher values for ESR (54.82 vs. 19.16, p<0.001), CRP (0.90 vs. 0.35, p=0.003), and P/V (37.4 vs. 22.8, p<0.001) as compared to those within the aseptic nonunion cohort. ROC curve analysis for P/V demonstrated that at an optimal ratio of 23, area under the curve (AUC) is 0.814, specificity is 55.6%, and sensitivity is 100.0%. There was no significant difference in the diagnostic performance of the serum biomarkers but only ESR and P/V had an AUC greater than 0.80. The negative predictive value (NPV) for P/V, ESR, and CRP was 100.0%, 84.6%, and 78.6%, respectively. Conclusion: The P/V ratio may serve as a reliable screening test for FRI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Proximal tibial metaphyseal bone loss compromises the alignment and fixation of components during revision total knee arthroplasty. In massive, segmental defects with loss of collateral ligamentous support and lack of bone to support the use of prosthetic augments or metaphyseal cones or sleeves, a hinged proximal tibial replacement or a so-called "megaprosthesis" should be available. While proximal tibial replacement is the reconstructive method of choice in the setting of bone tumor resection, applications in non-oncologic joint arthroplasty are rare and may offer an opportunity for limb salvage in dire clinical scenarios with massive proximal tibial bone loss. This report reviews 6 cases of proximal tibial replacement., (© 2019 The Authors.)

Objective: To identify the 50 most-cited articles in meniscal allograft transplantation (MAT) research and analyze their characteristics., Design: In September 2017, the Scopus database was queried to identify the 50 most-cited articles in MAT research. Variables analyzed include number of citations, publication year, journal, institution, country of origin, article type, study design, and level of evidence. Citation density was calculated for each article. The correlation between citation density and publication year and the correlation between level of evidence and number of citations, citation density, and publication year were computed., Results: The 50 most-cited articles were published in 12 journals between 1986 and 2011. The number of citations ranged from 59 to 290 (109.3 ± 48.6). Citation density ranged from 2.7 to 17.6 citations per year (7.0 ± 3.3). There was a positive correlation between citation density and publication year ( r = +0.489, P < 0.001). Overall, 56% of the articles were clinical and 44% were basic science. Of the 28 clinical articles, 61% were level IV or V evidence. Level of evidence was not significantly correlated with number of citations ( r = -0.059, P = 0.766), citation density ( r = +0.030, P = 0.880), or publication year ( r = -0.0009, P = 0.996)., Conclusion: This analysis provides the orthopedic community with a readily accessible list of the classic citations in MAT research and provides insight into the historical development of this procedure. Although there was a moderate positive correlation between citation density and publication year, articles with stronger levels of evidence were not more frequently cited despite the increasing trend toward evidence-based practice.

Background and Aim: Hepatitis delta virus (HDV) infection is the most rapidly progressive chronic viral hepatitis. Little is understood about the immune responses to HDV. This study aims to characterize the systemic immune environments of hepatitis B virus (HBV) and HDV patients at various disease stages., Methods: A total of 129 subjects were evaluated: 53 HBV, 43 HDV, and 33 healthy controls. HBV and HDV subjects were categorized by aspartate aminotransferase to platelet ratio index (APRI) into mild (APRI < 0.5), moderate, and severe (APRI > 1.0). Serum cytokines and immune markers were assessed at a single treatment-naïve time-point., Results: Type 1 cytokines are elevated in both HBV and HDV. Both groups show higher tumor necrosis factor-α (TNF-α), interleukin (IL)-12p40, and C-X-C motif chemokine ligand 9 when compared with controls (all P < 0.05). However, only HBV group displayed elevated γ-interferon compared with controls. Type 2 cytokines are elevated in HBV. HBV group shows higher IL-4, IL-13, and C-C motif chemokine ligand (CCL) 26 compared with healthy controls and HDV. Chemokines CCL2 and CCL13 are lower in HDV. When assessing ratios, HDV displays higher γ-interferon/IL-4, TNF-α/IL-4, and TNF-α/IL-13 ratios than HBV and controls., Conclusion: Hepatitis B virus and HDV subjects show similarly elevated type 1 cytokines. HDV subjects display relatively lower type 2 cytokines. These differences in the systemic immune environments, particularly the predominance of type 1 responses, may contribute to the comparatively rapid progression of HDV disease. Characterization of the imbalance in type 1 and type 2 immunity unique HDV has the potential to provide immunological insights for designing therapeutic targets in HDV-associated disease progression., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Prolonged exposure of CD8 + T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8 + T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα + CD8 + T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα + cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8 + T cell-killing in vivo. SIRPα + CD8 + T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8 + T cells during chronic infection expands the cytotoxic subset of SIRPα + CD8 + T cells.

Painful extensor carpi ulnaris tendon instability has various treatments with limited available outcome data. We treated 12 wrists of 11 patients (including eight collegiate or professional athletes) with dorsal transposition of the extensor carpi ulnaris tendon to lie over the 5th compartment, stabilized with a retinacular sling from 2010-2015. All patients had symptom resolution and returned to sport at the pre-injury level by 3 months after surgery. Mean post-surgical Patient Reported Outcomes Measurement Information System (PROMIS) upper extremity score was 56, and PROMIS pain interference score was 42. Patient overall satisfaction averaged 9.8 points on a 10-point scale for the procedure and pain decreased by 6 points on a 10-point scale from before surgery to final follow-up. We conclude that surgical treatment of the extensor carpi ulnaris tendon instability via dorsal transposition of the extensor carpi ulnaris tendon is an effective surgical option for all patients including the high level athlete. Level of evidence: IV.

Hepatitis delta virus (HDV) causes the most severe form of human viral hepatitis. HDV requires a hepatitis B virus (HBV) coinfection to provide HDV with HBV surface antigen envelope proteins. The net effect of HDV is to make the underlying HBV disease worse, including higher rates of hepatocellular carcinoma. Accurate assessments of current HDV prevalence have been hampered by the lack of readily available and reliable quantitative assays, combined with the absence of a Food and Drug Administration-approved therapy. We sought to develop a convenient assay for accurately screening populations and to use this assay to determine HDV prevalence in a population with abnormally high rates of hepatocellular carcinoma. We developed a high-throughput quantitative microarray antibody capture assay for anti-HDV immunoglobulin G wherein recombinant HDV delta antigen is printed by microarray on slides coated with a noncontinuous, nanostructured plasmonic gold film, enabling quantitative fluorescent detection of anti-HDV antibody in small aliquots of patient serum. This assay was then used to screen all HBV-infected patients identified in a large randomly selected cohort designed to represent the Mongolian population. We identified two quantitative thresholds of captured antibody that were 100% predictive of the sample either being positive on standard western blot or harboring HDV RNA detectable by real-time quantitative PCR. Subsequent screening of the HBV + cohort revealed that a remarkable 57% were RNA + and an additional 4% were positive on western blot alone., Conclusion: The quantitative microarray antibody capture assay's unique performance characteristics make it ideal for population screening; its application to the Mongolian HBV surface antigen-positive population reveals an apparent ∼60% prevalence of HDV coinfection among these HBV-infected Mongolian subjects, which may help explain the extraordinarily high rate of hepatocellular carcinoma in Mongolia. (Hepatology 2017;66:1739-1749)., (© 2016 by the American Association for the Study of Liver Diseases.)

Background & Aims: Phosphoinositides (PIs) bind and regulate localization of proteins via a variety of structural motifs. PI 4,5-bisphosphate (PI[4,5]P2) interacts with and modulates the function of several proteins involved in intracellular vesicular membrane trafficking. We investigated interactions between PI(4,5)P2 and hepatitis C virus (HCV) nonstructural protein 5A (NS5A) and effects on the viral life cycle., Methods: We used a combination of quartz crystal microbalance, circular dichroism, molecular genetics, and immunofluorescence to study specific binding of PI(4,5)P2 by the HCV NS5A protein. We evaluated the effects of PI(4,5)P2 on the function of NS5A by expressing wild-type or mutant forms of Bart79I or FL-J6/JFH-5'C19Rluc2AUbi21 RNA in Huh7 cells. We also studied the effects of strategies designed to inhibit PI(4,5)P2 on HCV replication in these cells., Results: The N-terminal amphipathic helix of NS5A bound specifically to PI(4,5)P2, inducing a conformational change that stabilized the interaction between NS5A and TBC1D20, which is required for HCV replication. A pair of positively charged residues within the amphipathic helix (the basic amino acid PI(4,5)P2 pincer domain) was required for PI(4,5)P2 binding and replication of the HCV-RNA genome. A similar motif was found to be conserved across all HCV isolates, as well as amphipathic helices of many pathogens and apolipoproteins., Conclusions: PI(4,5)P2 binds to HCV NS5A to promote replication of the viral RNA genome in hepatocytes. Strategies to disrupt this interaction might be developed to inhibit replication of HCV and other viruses., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: We evaluated whether staging with positron emission tomography (PET) or treatment with rituximab after involved-field radiation therapy (IFRT) results in an improved progression-free survival (PFS) for early-stage indolent non-Hodgkin lymphoma (NHL)., Methods: We identified 42 patients with stage I/II low-grade NHL treated with initial IFRT at our institution between 1992 and 2009, who had been staged with computed tomography (CT) or PET. A retrospective analysis was performed to evaluate PFS according to staging by CT or PET, and by receipt of rituximab after IFRT., Results: Overall PFS was 68% and 61% at 5 and 10 years, respectively. There was no significant difference in PFS whether patients were staged by CT (n=17) or by PET (n=25), with 5-year PFS rates of 76% and 60%, respectively. Eleven patients received 4 weekly doses of rituximab after IFRT, with no improvement in 5-year PFS: 46% for rituximab-treated patients versus 72% for patients who were not given rituximab. However, more patients who were given rituximab were stage II., Conclusions: Patients with limited stage indolent NHL staged with either CT or PET and treated with IFRT have favorable PFS compared with historical controls. The administration of 4 weekly doses of rituximab after IFRT did not improve PFS in these patients. The use of rituximab in this setting should be evaluated in a randomized prospective study.

Aurora kinases are highly conserved, essential regulators of cell division. Two Aurora kinase isoforms, A and B (AURKA and AURKB), are expressed ubiquitously in mammals, whereas a third isoform, Aurora C (AURKC), is largely restricted to germ cells. Because AURKC is very similar to AURKB, based on sequence and functional analyses, why germ cells express AURKC is unclear. We report that Aurkc(-/-) females are subfertile, and that AURKB function declines as development progresses based on increasing severity of cytokinesis failure and arrested embryonic development. Furthermore, we find that neither Aurkb nor Aurkc is expressed after the one-cell stage, and that AURKC is more stable during maturation than AURKB using fluorescently tagged reporter proteins. In addition, Aurkc mRNA is recruited during maturation. Because maturation occurs in the absence of transcription, posttranscriptional regulation of Aurkc mRNA, coupled with the greater stability of AURKC protein, provides a means to ensure sufficient Aurora kinase activity, despite loss of AURKB, to support both meiotic and early embryonic cell divisions. These findings suggest a model for the presence of AURKC in oocytes: that AURKC compensates for loss of AURKB through differences in both message recruitment and protein stability.