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Background: Controversy exists regarding the optimal technique of subscapularis tendon mobilization during shoulder arthroplasty. The purpose of the present randomized double-blind study was to compare two of these techniques-lesser tuberosity osteotomy and subscapularis peel-with regard to muscle strength and functional outcomes.Methods: Patients undergoing shoulder arthroplasty were randomized to undergo either a lesser tuberosity osteotomy or a subscapularis peel. The primary outcome was subscapularis muscle strength as measured with an electronic handheld dynamometer at twenty-four months postoperatively. Secondary outcomes included the Western Ontario Osteoarthritis of the Shoulder Index and American Shoulder and Elbow Surgeons scores. A sample size calculation determined that eighty-six patients provided 90% power with a 0.79 effect size to detect a significant difference between groups.Results: Forty-three patients were allocated to subscapularis osteotomy, and forty-four patients were allocated to subscapularis peel. Eighty-three percent of the study cohort returned for the twenty-four-month follow-up. The primary outcome of subscapularis muscle strength at twenty-four months revealed no significant difference (p = 0.131) between the lesser tuberosity osteotomy group (mean [and standard deviation], 4.4 ± 2.9 kg) and the subscapularis peel group (mean, 5.5 ± 2.6 kg). Comparison of secondary outcomes, including the Western Ontario Osteoarthritis of the Shoulder Index and American Shoulder and Elbow Surgeons scores, demonstrated no significant differences between groups at any time point. Compared with baseline measures, mean subscapularis muscle strength, Western Ontario Osteoarthritis of the Shoulder Index score, and American Shoulder and Elbow Surgeons score all improved significantly in both groups at twenty-four months (p < 0.001).Discussion: No significant differences in the primary or secondary outcomes of function were identified between the lesser tuberosity osteotomy group and the subscapularis peel group. For the parameters investigated, this trial does not demonstrate any clear advantage of one subscapularis treatment technique over the other. [ABSTRACT FROM AUTHOR]

Background: Femoroacetabular impingement is a cause of hip pain in adults and is a possible precursor of osteoarthritis, with the cam type of impingement being the most common. The purpose of this study was to determine the prevalence of cam-type morphology of the hip in asymptomatic patients.Methods: Two hundred asymptomatic volunteers with no prior hip surgery or childhood hip problems underwent magnetic resonance imaging targeted to both hips. The subjects were examined at the time of magnetic resonance imaging for internal rotation of the hips at 90° of hip flexion and for a positive impingement sign. The contour of the femoral head-neck junction was quantified with use of the alpha angle. A value of >50.5° was considered positive for cam morphology. Measurements were performed independently by two musculoskeletal radiologists.Results: The mean age of the individuals was 29.4 years (range, 21.4 to 50.6 years); 79% were white, and 55.5% were women. The mean alpha angle anteriorly at the three o'clock position was 40.9° ± 7.0° on the right and 40.6° ± 7.1° on the left, whereas the mean alpha angle anterosuperiorly at the 1:30 position was 50.2° ± 8.0° on the right and 50.1° ± 8.3° on the left. Fourteen percent of the volunteers had at least one hip with cam morphology: 10.5% had an elevated alpha angle on either the right or the left side, and 3.5% had the deformity in both hips. Seventy-nine percent (twenty-two) of twenty-eight individuals who had an elevated alpha angle were men, and 21% (six) were women. Individuals with an elevated alpha angle on at least one side tended to be male (p < 0.001), with 24.7% (twenty-two) of eighty-nine men having cam morphology compared with only 5.4% (six) of 111 women.Conclusions: The prevalence of cam-type femoroacetabular impingement deformity is higher in men as well as in individuals with decreased internal rotation. Defining what represents a normal head-neck contour is important for establishing treatment strategies in patients presenting with prearthritic hip pain. [ABSTRACT FROM AUTHOR]

Background: Acetabular retroversion is associated with impingement and instability. An adequate interpretation of acetabular version and coverage on radiographs is essential to determine the optimal treatment strategy (periacetabular osteotomy vs hip arthroscopic surgery). The crossover sign (COS) has been associated with the presence of acetabular retroversion, and the anterior wall index (AWI) and posterior wall index (PWI) assess anteroposterior acetabular coverage. However, the radiographic appearance of the acetabulum is sensitive to anterior inferior iliac spine (AIIS) morphology and pelvic tilt (PT), which differs between the supine and standing positions., Purpose: To (1) identify differences in the acetabular appearance between the supine and standing positions among patients presenting with hip pain; (2) determine factors (acetabular version, AIIS morphology, and spinopelvic characteristics) associated with the crossover ratio (COR), AWI, and PWI; and (3) define relevant clinical thresholds to guide management., Study Design: Cross-sectional study; Level of evidence, 3., Methods: Patients who presented to a hip preservation surgical unit (n = 134) were included (mean age, 35 ± 8 years; 58% female; mean body mass index, 27 ± 6). All participants underwent supine and standing anteroposterior pelvic radiography to assess the COS, COR, AWI, and PWI as well as standing lateral radiography to determine standing PT. Computed tomography was used to measure supine PT, acetabular version, and AIIS morphology. Acetabular version was measured at 3 transverse levels, corresponding to the 1-, 2-, and 3-o'clock positions. The correlation between radiographic characteristics (COR, AWI, and PWI) and acetabular version, AIIS morphology, and PT was calculated using the Spearman correlation coefficient. Receiver operating characteristic curve analysis was performed to define thresholds for the COR, AWI, and PWI to identify retroversion (version thresholds: <10°, <5°, and <0°)., Results: The COS was present in 55% of hips when supine and 30% when standing, with a mean difference in the COR of 12%. The supine COR (rho = -0.661) and AWI/PWI ratio (rho = -0.618) strongly correlated with acetabular version. The COS was more prevalent among patients with type 2 AIIS morphology (71%) than among those with type 1 AIIS morphology (43%) ( P = .003). COR thresholds of 23% and 28% were able to identify acetabular version <5° (sensitivity = 81%; specificity = 80%) and <0° (sensitivity = 88%; specificity = 85%), respectively. An AWI/PWI ratio >0.6 was able to reliably identify acetabular version <0° (sensitivity = 83%; specificity = 84%). In the presence of a COR >30% and an AWI/PWI ratio >0.6, the specificity to detect retroversion was significantly increased (>90%)., Conclusions: The presence of the COS was very common among patients with hip pain. False-positive results (high COR/normal version) may occur because of AIIS morphology/low PT. Relevant thresholds of COR >30% and AWI/PWI ratio >0.6 can help with diagnostic accuracy. In cases in which either the COR or AWI/PWI ratio is high, axial cross-sectional imaging can further help to avoid false-positive results., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: P.E.B. has received royalties from Corin, MicroPort, Medacta, and MatOrtho; consulting fees from DePuy Synthes, MicroPort, MatOrtho, and Zimmer Biomet; and research support from Zimmer Biomet, MicroPort, Medacta, and Corin. G.G. has received consulting fees from DePuy Synthes and research support from Stryker and Zimmer Biomet. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

As powerful activators of the immune system, cytokines have been extensively explored for treating various cancers. But despite encouraging advances and some drug approvals, the broad adoption of cytokine therapies in the clinic has been limited by low response rates and sometimes severe toxicities. This in part reflects an inefficient biodistribution to tumors or a pleiotropic action on bystander cells and tissues. Here, we first review these issues and then argue for the intratumoral delivery of engineered cytokine fusion proteins that have been optimized for tumor retention as a potential solution to overcome these limitations and realize the potential of cytokines as highly effective therapeutics for cancer., Competing Interests: All authors are current or former paid full-time employees of, and own shares and/or stock options of Cullinan Therapeutics, Inc. Cullinan develops CLN-617, one of the modalities discussed in this perspective. The authors declare that this study received funding from Cullinan Therapeutics, Inc. The funder had the following involvement in the study: Cullinan funded the work, paid publication fees, and all authors are current or former Cullinan employees., (Copyright © 2024 Sauer, Rakhra, Wu, Mehta, Michaelson and Baeuerle.)

Despite clinical evidence of antitumor activity, the development of cytokine therapies has been hampered by a narrow therapeutic window and limited response rates. Two cytokines of high interest for clinical development are interleukin 2 (IL2) and interleukin 12 (IL12), which potently synergize to promote the activation and proliferation of T cells and NK cells. However, the only approved human IL2 therapy, Proleukin, is rarely used in the clinic due to systemic toxicities, and no IL12 product has been approved to date due to severe dose-limiting toxicities. Here, we describe CLN-617, a first-in-class therapeutic for intratumoral (IT) injection that co-delivers IL2 and IL12 on a single molecule in a safe and effective manner. CLN-617 is a single-chain fusion protein comprised of IL2, leukocyte-associated immunoglobulin-like receptor 2 (LAIR2), human serum albumin (HSA), and IL12. LAIR2 and HSA function to retain CLN-617 in the treated tumor by binding collagen and increasing molecular weight, respectively. We found that IT administration of a murine surrogate of CLN-617, mCLN-617, eradicated established treated and untreated tumors in syngeneic models, significantly improved response to anti-PD1 checkpoint therapy, and generated a robust abscopal response dependent on cellular immunity and antigen cross-presentation. CLN-617 is being evaluated in a clinical trial in patients with advanced solid tumors (NCT06035744)., (©2024 The Authors; Published by the American Association for Cancer Research.)

The aim of this study was to validate a novel medical virtual reality (VR) platform used for medical image segmentation and contouring in radiation oncology and 3D anatomical modeling and simulation for planning medical interventions, including surgery. The first step of the validation was to verify quantitatively and qualitatively that the VR platform can produce substantially equivalent 3D anatomical models, image contours, and measurements to those generated with existing commercial platforms. To achieve this, a total of eight image sets and 18 structures were segmented using both VR and reference commercial platforms. The image sets were chosen to cover a broad range of scanner manufacturers, modalities, and voxel dimensions. The second step consisted of evaluating whether the VR platform could provide efficiency improvements for target delineation in radiation oncology planning. To assess this, the image sets for five pediatric patients with resected standard-risk medulloblastoma were used to contour target volumes in support of treatment planning of craniospinal irradiation, requiring complete inclusion of the entire cerebral-spinal volume. Structures generated in the VR and the commercial platforms were found to have a high degree of similarity, with dice similarity coefficient ranging from 0.963 to 0.985 for high-resolution images and 0.920 to 0.990 for lower resolution images. Volume, cross-sectional area, and length measurements were also found to be in agreement with reference values derived from a commercial system, with length measurements having a maximum difference of 0.22 mm, angle measurements having a maximum difference of 0.04°, and cross-sectional area measurements having a maximum difference of 0.16 mm 2 . The VR platform was also found to yield significant efficiency improvements, reducing the time required to delineate complex cranial and spinal target volumes by an average of 50% or 29 min., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

The Canadian Association of Radiologists (CAR) Musculoskeletal System Expert Panel consists of musculoskeletal radiologists, a family physician, a sports and exercise medicine physician, emergency medicine physicians, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 25 musculoskeletal clinical/diagnostic scenarios, a systematic rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for 1 or more of these clinical/diagnostic scenarios. Recommendations from 41 guidelines (50 publications) and contextualization criteria in the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for guidelines framework were used to develop 124 recommendation statements across the 25 scenarios related to the evaluation of the musculoskeletal system. This guideline presents the methods of development and the recommendations for imaging in the context of musculoskeletal pain, infection, tumors, arthropathies, metabolic bone disease, stress injuries, orthopedic hardware, avascular necrosis/bone infarction, and complex regional pain syndrome., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Acetabular morphology is an important determinant of hip biomechanics. To identify features of acetabular morphology that may be associated with the development of hip symptoms while accounting for spinopelvic characteristics, one needs to determine acetabular characteristics in a group of individuals older than 45 years without symptoms or signs of osteoarthritis. Previous studies have used patients with unknown physical status to define morphological thresholds to guide management., Questions/purposes: (1) To determine acetabular morphological characteristics in males and females between 45 and 60 years old with a high Oxford hip score (OHS) and no signs of osteoarthritis; (2) to compare these characteristics with those of symptomatic hip patients treated with hip arthroscopy or periacetabular osteotomy (PAO) for various kinds of hip pathology (dysplasia, retroversion, and cam femoroacetabular impingement); and (3) to assess which radiographic or CT parameters most accurately differentiate between patients who had symptomatic hips and those who did not, and thus, define thresholds that can guide management., Methods: Between January 2018 and December 2018, 1358 patients underwent an abdominopelvic CT scan in our institution for nonorthopaedic conditions. Of those, we considered 5% (73) of patients as potentially eligible as controls based on the absence of major hip osteoarthritis, trauma, or deformity. Patients were excluded if their OHS was 43 or less (2% [ 28 ]), if they had a PROMIS less than 50 (1% [ 18 ]), or their Tönnis score was higher than 1 (0.4% [ 6 ]). Another eight patients were excluded because of insufficient datasets. After randomly selecting one side for each control, 40 hips were left for analysis (age 55 ± 5 years; 48% [19 of 40] were in females). In this comparative study, this asymptomatic group was compared with a group of patients treated with hip arthroscopy or PAO. Between January 2013 and December 2020, 221 hips underwent hip preservation surgery. Of those, eight were excluded because of previous pelvic surgery, and 102 because of insufficient CT scans. One side was randomly selected in patients who underwent bilateral procedure, leaving 48% (107 of 221) of hips for analysis (age 31 ± 8 years; 54% [58 of 107] were in females). Detailed radiographic and CT assessments (including segmentation) were performed to determine acetabular (depth, cartilage coverage, subtended angles, anteversion, and inclination) and spinopelvic (pelvic tilt and incidence) parameters. Receiver operating characteristics (ROC) analysis was used to assess diagnostic accuracy and determine which morphological parameters (and their threshold) differentiate most accurately between symptomatic patients and asymptomatic controls., Results: Acetabular morphology in asymptomatic hips was characterized by a mean depth of 22 ± 2 mm, with an articular cartilage surface of 2619 ± 415 mm 2 , covering 70% ± 6% of the articular surface, a mean acetabular inclination of 48° ± 6°, and a minimal difference between anatomical (24° ± 7°) and functional (22° ± 6°) anteversion. Patients with symptomatic hips generally had less acetabular depth (20 ± 4 mm versus 22 ± 2 mm, mean difference 3 mm [95% CI 1 to 4]; p < 0.001). Hips with dysplasia (67% ± 5% versus 70% ± 6%, mean difference 6% [95% CI 0% to 12%]; p = 0.03) or retroversion (67% ± 5% versus 70% ± 6%, mean difference 6% [95% CI 1% to 12%]; p = 0.04) had a slightly lower relative cartilage area compared with asymptomatic hips. There was no difference in acetabular inclination (48° ± 6° versus 47° ± 7°, mean difference 0.5° [95% CI -2° to 3°]; p = 0.35), but asymptomatic hips had higher anatomic anteversion (24° ± 7° versus 19° ± 8°, mean difference 6° [95% CI 3° to 9°]; p < 0.001) and functional anteversion (22° ± 6° versus 13°± 9°, mean difference 9° [95% CI 6° to 12°]; p < 0.001). Subtended angles were higher in asymptomatic at 105° (124° ± 7° versus 114° ± 12°, mean difference 11° [95% CI 3° to 17°]; p < 0.001), 135° (122° ± 9° versus 111° ± 12°, mean difference 10° [95% CI 2° to 15°]; p < 0.001), and 165° (112° ± 9° versus 102° ± 11°, mean difference 10° [95% CI 2° to 14°]; p < 0.001) around the acetabular clockface. Symptomatic hips had a lower pelvic tilt (8° ± 8° versus 11° ± 5°, mean difference 3° [95% CI 1° to 5°]; p = 0.007). The posterior wall index had the highest discriminatory ability of all measured parameters, with a cutoff value of less than 0.9 (area under the curve [AUC] 0.84 [95% CI 0.76 to 0.91]) for a symptomatic acetabulum (sensitivity 72%, specificity 78%). Diagnostically useful parameters on CT scan to differentiate between symptomatic and asymptomatic hips were acetabular depth less than 22 mm (AUC 0.74 [95% CI 0.66 to 0.83]) and functional anteversion less than 19° (AUC 0.79 [95% CI 0.72 to 0.87]). Subtended angles with the highest accuracy to differentiate between symptomatic and asymptomatic hips were those at 105° (AUC 0.76 [95% CI 0.65 to 0.88]), 135° (AUC 0.78 [95% CI 0.70 to 0.86]), and 165° (AUC 0.77 [95% CI 0.69 to 0.85]) of the acetabular clockface., Conclusion: An anatomical and functional acetabular anteversion of 24° and 22°, with a pelvic tilt of 10°, increases the acetabular opening and allows for more impingement-free flexion while providing sufficient posterosuperior coverage for loading. Hips with lower anteversion or a larger difference between anatomic and functional anteversion were more likely to be symptomatic. The importance of sufficient posterior coverage was also illustrated by the posterior wall indices and subtended angles at 105°, 135°, and 165° of the acetabular clockface having a high discriminatory ability to differentiate between symptomatic and asymptomatic hips. Future research should confirm whether integrating these parameters when selecting patients for hip preservation procedures can improve postoperative outcomes.Level of Evidence Level III, prognostic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. 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 © 2023 by the Association of Bone and Joint Surgeons.)

Background: Radiographic evaluation plays an important role in detecting and grading hip dysplasia. Acetabular sector angles (ASAs) measure the degree of femoral head coverage provided by the acetabulum on computed tomographic (CT) scans. In this study, we aimed to determine ASA values at different axial levels in a control cohort with asymptomatic, high-functioning hips without underlying hip pathology and a study group with symptomatic, dysplastic hips that underwent periacetabular osteotomy (PAO), thereby defining the ASA thresholds for hip dysplasia., Methods: This was a cross-sectional study evaluating a control group of 51 patients (102 hips) and a study group of 66 patients (72 hips). The control group was high-functioning and asymptomatic, with an Oxford Hip Score of >43, did not have osteoarthritis (Tönnis grade ≤1), underwent a pelvic CT scan, had a mean age (and standard deviation) of 52.1 ± 5.5 years, and was 52.9% female. The study group had symptomatic hip dysplasia treated with PAO, had a mean age of 29.5 ± 7.3 years, and 83.3% was female. Anterior ASA (AASA) and posterior ASA (PASA) were measured at 3 axial CT levels to determine equatorial, intermediate, and proximal ASA. The thresholds for dysplasia were determined using receiver operating characteristic (ROC) curve analysis, including the area under the curve (AUC)., Results: Patients with dysplasia had significantly smaller ASAs compared with the control group; the differences were most pronounced for proximal AASAs and proximal and intermediate PASAs. The control group had a mean proximal PASA of 162° ± 17°, yielding a threshold for dysplasia of 137° (AUC, 0.908). The mean intermediate PASA for the control group was 117° ± 11°, yielding a threshold of 107° (AUC, 0.904). The threshold for anterior dysplasia was 133° for proximal AASA (AUC, 0.859) and 57° for equatorial AASA (AUC, 0.868). The threshold for posterior dysplasia was 102° for intermediate PASA (AUC, 0.933)., Conclusions: Measurement of ASA is a reliable tool to identify focal acetabular deficiency with high accuracy, aiding diagnosis and management. A proximal PASA of <137° or an intermediate PASA of <107° should alert clinicians to the presence of dysplasia., Level of Evidence: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H630 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

A lumbosacral transitional vertebra (LSTV) has been reported to be prevalent among patients with hip dysplasia. The aims of this study were to determine the (1) prevalence of an LSTV in young patients presenting with hip pain and a group of asymptomatic volunteers, (2) effect of an LSTV on spinopelvic characteristics, and (3) presence of low back pain among patients with an LSTV., Methods: This cross-sectional study included 102 patients with hip pathology and 51 asymptomatic volunteers (mean age, 33.9 ± 7.3 years; mean body mass index, 26.0 ± 5.0 kg/m 2 ; 57.5% female). Participants underwent radiographic assessment of the lumbar spine and pelvis in standing and deep-seated positions. LSTV occurrence was classified according to the Castellvi system. Spinopelvic characteristics included lumbar lordosis (including segmental lumbar angles), pelvic tilt, and hip flexion (pelvic-femoral angle). Differences between standing and deep-seated values were calculated. Low back pain was assessed using the Oswestry Disability Index., Results: The prevalence of LSTV type ≥II was 8.5%, with no difference between patients and volunteers (p = 0.386). Individuals with an LSTV had a greater standing L1-L5 angle (mean, 51.6° ± 11.7° versus 38.9° ± 9.3°; p < 0.001). The overall spinal flexion (change in L1-S1 angle between the standing and deep-seated positions) in individuals with an LSTV was similar to that in individuals without an LSTV; restricted L5-S1 mobility was compensated for at L1-L2 (10.2° ± 5.8° in those with versus 8.4° ± 4.1° in those without an LSTV; p = 0.070). No significant difference in the presence of low back pain was found (p = 0.250)., Conclusions: An LSTV was found in 8.5% of young adults, with no difference between patients with hip pathology and controls. Individuals with an LSTV have greater standing lumbar lordosis, with altered mechanics at the cephalad adjacent level, which may predispose these individuals to degenerative changes at this level., Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A480)., (Copyright © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

The field of immuno-oncology has revolutionized cancer patient care and improved survival and quality of life for patients. Much of the focus in the field has been on exploiting the power of the adaptive immune response through therapeutic targeting of T cells. While these approaches have markedly advanced the field, some challenges remain, and the clinical benefit of T cell therapies does not extend to all patients or tumor indications. Alternative strategies, such as engaging the innate immune system, have become an intense area of focus in the field. In particular, the engagement of natural killer (NK) cells as potent effectors of the innate immune response has emerged as a promising modality in immunotherapy. Here, we review therapeutic approaches for selective engagement of NK cells for cancer therapy, with a particular focus on targeting the key activating receptors NK Group 2D (NKG2D) and cluster of differentiation 16A (CD16A).

Objective: Permanent supportive housing has been identified as a possible intervention which could reduce the risk of criminal justice involvement (CJI) among people with serious mental illness who are experiencing residential instability and homelessness. However, the evidence evaluating the impact of supportive housing on CJI is mixed. Increasing understanding of the specific needs of people with justice involvement entering supportive housing may inform interventions which improve their criminal justice outcomes. Toward this end, this study compared the characteristics and need profiles of applicants to supportive housing with and without current CJI., Methods: Secondary analyses were conducted of archival databases of 12,277 individuals applying for supportive housing in Toronto, Canada between 2009 and 2015. The characteristics and support needs of applicants with current CJI were compared to applicants with no current justice involvement., Results: Of the applicants, 2,894 (23.6%) reported having justice involvement at the time of referral to supportive housing services. The strongest predictors of having justice involvement were a history of physical assaults, homelessness, problematic substance use, male gender, and younger age., Conclusions and Implications for Practice: Criminological factors rather than functional or mental health needs were most predictive of having current justice involvement at referral. Development of justice-focused supportive housing models may be considered which supplement traditional supportive housing approaches with empirically based interventions targeting the criminogenic needs of people with mental illness and justice involvement. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Tissue-resident memory T cells (T RMs ) can profoundly enhance mucosal immunity, but parameters governing T RM induction by vaccination remain poorly understood. Here, we describe an approach exploiting natural albumin transport across the airway epithelium to enhance mucosal T RM generation by vaccination. Pulmonary immunization with albumin-binding amphiphile conjugates of peptide antigens and CpG adjuvant (amph-vaccines) increased vaccine accumulation in the lung and mediastinal lymph nodes (MLNs). Amph-vaccines prolonged antigen presentation in MLNs over 2 weeks, leading to 25-fold increased lung-resident T cell responses over traditional immunization and enhanced protection from viral or tumor challenge. Mimicking such prolonged exposure through repeated administration of soluble vaccine revealed that persistence of both antigen and adjuvant was critical for optimal T RM induction, mediated through T cell priming in MLNs after prime, and directly in the lung tissue after boost. Thus, vaccine persistence strongly promotes T RM induction, and amph-conjugates may provide a practical approach to achieve such kinetics in mucosal vaccines., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The tetracycline regulatory system provides a tractable strategy to interrogate the role of oncogenes in the initiation, maintenance, and regression of tumors through both spatial and temporal control of expression. This approach has several potential advantages over conventional methods to generate genetically engineered mouse models. First, continuous constitutive overexpression of an oncogene can be lethal to the host impeding further study. Second, constitutive overexpression fails to model adult onset of disease. Third, constitutive deletion does not permit, whereas conditional overexpression of an oncogene enables the study of the consequences of restoring expression of an oncogene back to endogenous levels. Fourth, the conditional activation of oncogenes enables examination of specific and/or developmental state-specific consequences.Hence, by allowing precise control of when and where a gene is expressed, the tetracycline regulatory system provides an ideal approach for the study of putative oncogenes in the initiation as well as the maintenance of tumorigenesis and the examination of the mechanisms of oncogene addiction. In this protocol, we describe the methods involved in the development of a conditional mouse model of MYC-induced T-cell acute lymphoblastic leukemia.

Background: Hip dysplasia is one of the most common causes of hip arthritis. Its incidence is estimated to be between 3.6 and 12.8% (Canadian Institute for Health Information, Hip and knee replacements in Canada, 2017-2018: Canadian joint replacement registry annual report, 2019; Jacobsen and Sonne-Holm, Rheumatology 44:211-8, 2004). The Periacetabular Osteotomy (PAO) has been used successfully for over 30 years (Gosvig et al., J Bone Joint Surg Am 92:1162-9, 2010), but some patients continue to exhibit symptoms post-surgery (Wyles et al., Clin Orthop Relat Res 475:336-50, 2017). A hip arthroscopy, performed using a small camera, allows surgeons to address torn cartilage inside the hip joint. Although both procedures are considered standard of care treatment options, it is unknown whether the addition of hip arthroscopy improves patient outcomes compared to a PAO alone. To delay or prevent future joint replacement surgeries, joint preservation surgery is recommended for eligible patients. While previous studies found an added cost to perform hip arthroscopies, the cost-effectiveness to Canadian Health care system is not known., Methods: Patients randomized to the experimental group will undergo central compartment hip arthroscopy prior to completion of the PAO. Patients randomized to the control group will undergo isolated PAO. Patient-reported quality of life will be the primary outcome used for comparison between the two treatment groups as measured by The International Hip Outcome Tool (iHOT-33) (Saberi Hosnijeh et al., Arthritis Rheum 69:86-93, 2017). Secondary outcomes will include the four-square step test and sit-to-stand (validated in patients with pre-arthritic hip pain) and hip-specific symptoms and impairment using the HOOS; global health assessment will be compared using the PROMIS Global 10 Score; health status will be assessed using the EQ-5D-5L and EQ VAS questionnaires (Ganz et al., Clin Orthop Relat Res 466:264-72, 2008) pre- and post-operatively. In addition, operative time, hospital length of stay, adverse events, and health services utilization will be collected. A sub-group of patients (26 in each group) will receive a T1rho MRI before and after surgery to study changes in cartilage quality over time. A cost-utility analysis will be performed to compare costs and quality-adjusted life years (QALYs) associated with the intervention., Discussion: We hypothesize that (1) concomitant hip arthroscopy at the time of PAO to address central compartment pathology will result in clinically important improvements in patient-reported outcome measures (PROMs) versus PAO alone, that (2) additional costs associated with hip arthroscopy will be offset by greater clinical improvements in this group, and that (3) combined hip arthroscopy and PAO will prove to be a cost-effective procedure., Trial Registration: ClinicalTrials.gov NCT03481010 . Registered on 6 March 2020. Protocol version: version 3.

The formulations of peptide-based antitumour vaccines being tested in clinical studies are generally associated with weak potency. Here, we show that pharmacokinetically tuning the responses of peptide vaccines by fusing the peptide epitopes to carrier proteins optimizes vaccine immunogenicity in mice. In particular, we show in immunized mice that the carrier protein transthyretin simultaneously optimizes three factors: efficient antigen uptake in draining lymphatics from the site of injection, protection of antigen payloads from proteolytic degradation and reduction of antigen presentation in uninflamed distal lymphoid organs. Optimizing these factors increases vaccine immunogenicity by up to 90-fold and maximizes the responses to viral antigens, tumour-associated antigens, oncofetal antigens and shared neoantigens. Protein-peptide epitope fusions represent a facile and generalizable strategy for enhancing the T-cell responses elicited by subunit vaccines.

Background: Acetabular version influences joint mechanics and the risk of impingement. Cross-sectional studies have reported an increase in acetabular version during adolescence; however, to our knowledge no longitudinal study has assessed version or how the change in version occurs. Knowing this would be important because characterizing the normal developmental process of the acetabulum would allow for easier recognition of a morphologic abnormality., Questions/purposes: To determine (1) how acetabular version changes during adolescence, (2) calculate how acetabular coverage of the femoral head changed during this period, and (3) to identify whether demographic factors or hip ROM are associated with acetabular development., Methods: This retrospective analysis of data from a longitudinal study included 17 volunteers (34 hips) with a mean (± SD) age of 11 ± 2 years; seven were male and 10 were female. The participants underwent a clinical examination of BMI and ROM and MRIs of both hips at recruitment and at follow-up (6 ± 2 years). MR images were assessed to determine maturation of the triradiate cartilage complex, acetabular version, and degree of the anterior, posterior, and superior acetabular sector angles (reflecting degree of femoral head coverage provided by the acetabulum anteriorly, posteriorly and superiorly respectively). An orthopaedic fellow (GG) and a senior orthopaedic resident (PJ) performed all readings in consensus; 20 scans were re-analyzed for intraobserver reliability. Thereafter, a musculoskeletal radiologist (KR) repeated measurements in 10 scans to test interobserver reliability. The intra- and interobserver interclass correlation coefficients for absolute agreement were 0.85 (95% CI 0.76 to 0.91; p < 0.001) and 0.77 (95% CI 0.70 to 0.84), respectively. All volunteers underwent a clinical examination by a senior orthopaedic resident (PJ) to assess their range of internal rotation (in 90° of flexion) in the supine and prone positions using a goniometer. We tested investigated whether the change in anteversion and sector angles differed between genders and whether the changes were correlated with BMI or ROM using Pearson's coefficient. The triradiate cartilage complex was open (Grade I) at baseline and closed (Grade III) at follow-up in all hips., Results: The acetabular anteversion increased, moving caudally further away from the roof at both timepoints. The mean (range) anteversion angle increased from 7° ± 4° (0 to 18) at baseline to 12° ± 4° (5 to 22) at the follow-up examination (p < 0.001). The mean (range) anterior sector angle decreased from 72° ± 8° (57 to 87) at baseline to 65° ± 8° (50 to 81) at the final follow-up (p = 0.002). The mean (range) posterior (98° ± 5° [86 to 111] versus 97° ± 5° [89 to 109]; p = 0.8) and superior (121° ± 4° [114 to 129] to 124° ± 5° [111 to 134]; p = 0.07) sector angles remained unchanged. The change in the anterior sector angle correlated with the change in version (rho = 0.5; p = 0.02). The change in version was not associated with any of the tested patient factors (BMI, ROM)., Conclusions: With skeletal maturity, acetabular version increases, especially rostrally. This increase is associated with, and is likely a result of, a reduced anterior acetabular sector angle (that is, less coverage anteriorly, while the degree of coverage posteriorly remained the same). Thus, in patients were the normal developmental process is disturbed, a rim-trim might be an appropriate surgical solution, since the degree of posterior coverage is sufficient and no reorientation osteotomy would be necessary. However, further study on patients with retroversion (of various degrees) is necessary to characterize these observations further. The changes in version were not associated with any of the tested patient factors; however, further study with greater power is needed., Level of Evidence: Level II, prognostic study.

Aim: To assess the diagnostic yield and complication rate of image-guided percutaneous rib biopsy, comparing ultrasonography (US) to fluoroscopy and computed tomography (CT)-guided biopsy techniques., Materials and Methods: A retrospective review was conducted of patients who underwent image-guided percutaneous rib biopsy at a single tertiary-care academic centre between January 2007 and June 2017. The diagnostic yield and complication rates were calculated and compared between the three imaging methods., Results: A total of 70 consecutive, image-guided percutaneous rib biopsies were performed in 67 patients (48 in males, 22 in females, mean age of 68.2 years, age range 31-92 years). The image guidance method utilised for biopsy was US in 64.3% (45/70), CT in 18.6% (13/70), and fluoroscopy in 17.1% (12/70). The diagnostic yield for all cases combined was 97.1% (68/70) and 97.8% (44/45) for US-guided biopsies specifically. A complication of pneumothorax was encountered in 4.3% (3/70) of all cases combined and in 4.4% (2/45) of US-guided biopsies specifically., Discussion: US-guided percutaneous rib biopsy has a high diagnostic yield and low complication rate, comparable to fluoroscopy or CT-guided biopsy., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: The management of asymptomatic individuals with cam femoral morphology that predisposes their hips to femoroacetabular impingement has received little attention. Such hips may have subclinical articular damage; however, whether this cartilage damage will progress is unknown as is whether any particular bone morphologies are associated with this progression. Such knowledge could help determine the natural history and guide management of such individuals., Questions/purposes: The purpose of this study was to determine whether (1) asymptomatic hips with cam morphology are at risk of further cartilage degeneration (as evaluated by T1ρ); (2) T1ρ changes are predictive of symptom onset; and (3) bony morphologic parameters are associated with T1ρ signal changes., Methods: In a prospective, longitudinal study, 17 asymptomatic volunteers/hips (16 men; 33 ± 6 years) with cam morphology underwent two T1ρ MRI scans and functional assessment (WOMAC) at recruitment and at 4 years (range, 2-6 years). Volunteers were recruited from a previous study, which reported on the prevalence of cam morphology among asymptomatic individuals using hip MRI; cam morphology was defined as an α angle ≥ 60° anterolaterally and/or ≥ 50.5° anteriorly relative to the neck axis. The differences in T1ρ values (ΔT1ρ) and relative differences (%ΔT1ρ) were calculated as: ΔT1ρ = T1ρFollowup - T1ρInitial and %ΔT1ρ = ΔT1ρ/T1ρInitial. A %ΔT1ρ > 17.6% was considered clinically important. Using CT data, femoral, acetabular, and spinopelvic parameters were measured. Whether ΔT1ρ and/or %ΔT1ρ was associated with any of the bone morphologic parameters was tested using Spearman's correlation coefficient., Results: The global T1ρ in these asymptomatic hips with cam morphology remained unchanged between initial (mean, 35 ± 5 ms) and followup scans (mean, 34 ± 3 ms; p = 0.518). No differences with the numbers available in T1ρ values were seen initially between the anterolateral and posterolateral (34 ± 6 ms versus 33 ± 4 ms; p = 0.734) regions; at followup, T1 values were higher posterolaterally (36 ± 5 ms versus 32 ± 5 ms; p = 0.031). The mean global ΔT1ρ was 1 ± 5 ms (95% confidence interval, -1 to +3 ms) and the mean global %ΔT1ρ was 2% ± 13%. Two volunteers reported lower WOMAC scores; one patient exhibited a clinically important increase in %ΔT1ρ (-26%). The degree of acetabular coverage correlated with %ΔT1ρ (rho = 0.59-0.61, p = 0.002); the lesser the acetabular coverage anterolaterally, the greater the corresponding area's T1ρ at followup., Conclusions: Although signs of posterolateral joint degeneration were detected, these were not generally associated with symptoms, and only one of the two volunteers with the onset of symptoms had a clinically important increase in %ΔT1ρ. We found that reduced acetabular coverage may increase the likelihood that preclinical cartilage degeneration will arise within 2 to 6 years; thereby reduced acetabular coverage should be considered when stratifying asymptomatic hips at risk of degeneration. Future studies should be performed with a larger cohort and include femoral version among the parameters studied., Level of Evidence: Level II, diagnostic study.

Objective: Femoroacetabular impingement (FAI) involves abnormal hip biomechanics due to deformities and is associated with osteoarthritis. Bone mineral density (BMD) in the acetabulum is higher in subjects with convex femoral (cam) FAI deformities compared to control subjects. The objective of this study was to assess post-operative changes of BMD with and without surgical correction of the cam deformity., Design: Thirteen patients with bilateral cam deformities but unilateral symptoms underwent pre-operative and follow-up computed tomography (CT) scans of both hips. The deformity was surgically removed from the symptomatic hip. BMD was measured in regions of interest (ROI) around the superior acetabulum from CT scans at both time points. The contralateral untreated hip was used as a within-patient control. Changes in BMD were assessed by two-way repeated measures ANOVA (side, time) and paired t-tests., Results: A greater BMD decrease was seen in the treated compared to the untreated hip (P < 0.0018). BMD within the superior acetabulum decreased by 39 mg/cc on the treated side (P < 0.0001) but only 9 mg/cc (P = 0.15) in the untreated contralateral hip. These changes represent 7.1% and 1.7% of the pre-operative BMD on the respective sides., Conclusions: BMD decreased in the treated hip, suggesting a positive effect of surgical correction in relieving stresses within the hip joint. Longer term follow-up is required to assess the ultimate fate of the articular cartilage within the joint. This study showed that surgical correction of the cam deformity in patients with FAI may alter the pathological biomechanics within the joint., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

This article reviews a body of work performed by the investigators over 9 years that has addressed the significance of cam morphology in the development of hip osteoarthritis (OA). Early hip joint degeneration is a common clinical presentation and preexisting abnormal joint morphology is a risk factor for its development. Interrogating Hill's criteria, we tested whether cam-type femoroacetabular impingement leads to hip OA. Strength of association was identified between cam morphology, reduced range-of-movement, hip pain, and cartilage degeneration. By studying a pediatric population, we were able to characterize the temporality between cam morphology (occurring 1st) and joint degeneration. Using in silico (finite element) and in vivo (imaging biomarkers) studies, we demonstrated the biological plausibility of how a cam deformity can lead to joint degeneration. Furthermore, we were able to show a biological gradient between degree of cam deformity and extent of articular damage. However, not all patients develop joint degeneration and we were able to characterize which factors contribute to this (specificity). Lastly, we were able to show that by removing the cam morphology, one could positively influence the degenerative process (experiment). The findings of this body of work show consistency and coherence with the literature. Furthermore, they illustrate how cam morphology can lead to early joint degeneration analogous to SCFE, dysplasia, and joint mal-reduction post-injury. The findings of this study open new avenues on the association between cam morphology and OA including recommendations for the study, screening, follow-up, and assessment (patient-specific) of individuals with cam morphology in order to prevent early joint degeneration. Statement of significance: By satisfying Hill's criteria, one can deduct that in some individuals, cam morphology is a cause of OA. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3125-3135, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Cam morphology in association with femoroacetabular impingement (FAI) is a recognized cause of hip pain and cartilage damage and proposed as a leading cause of arthritis. The purpose of this study was to analyze the functional and biomechanical effects of the surgical correction of the cam deformity on the degenerative process associated with FAI., Methods: Ten male patients with a mean age of 34.3 years (range, 23.1 to 46.5 years) and a mean body mass index (and standard deviation) of 26.66 ± 4.79 kg/m underwent corrective surgery for cam deformity in association with FAI. Each patient underwent a computed tomography (CT) scan to assess acetabular bone mineral density (BMD), high-resolution T1ρ magnetic resonance imaging (MRI) of the hips to assess proteoglycan content, and squatting motion analysis as well as completed self-administered functional questionnaires (Hip disability and Osteoarthritis Outcome Score [HOOS]) both preoperatively and 2 years postoperatively., Results: At a mean follow-up of 24.5 months, improvements in functional scores and squat performance were seen. Regarding the zone of impingement in the anterosuperior quadrant of the acetabular rim, the mean change in BMD at the time of follow-up was -31.8 mg/cc (95% confidence interval [CI], -11 to -53 mg/cc) (p = 0.008), representing a 5% decrease in BMD. The anterosuperior quadrant also demonstrated a significant decrease in T1ρ values, reflecting a stabilization of the cartilage degeneration. Significant correlations were noted between changes in clinical functional scores and changes in T1ρ values (r = -0.86; p = 0.003) as well as between the BMD and maximum vertical force (r = 0.878; p = 0.021)., Conclusions: Surgical correction of a cam deformity in patients with symptomatic FAI not only improved clinical function but was also associated with decreases in T1ρ values and BMD. These findings are the first, to our knowledge, to show that alteration of the hip biomechanics through surgical intervention improves the overall health of the hip joint., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

This corrects the article DOI: 10.1038/ncomms14069.

Objective: The purpose of this study is to develop a tool to assess the procedural competence of radiology trainees, with sources of evidence gathered from five categories to support the construct validity of tool: content, response process, internal structure, relations to other variables, and consequences., Subjects and Methods: A pilot form for assessing procedural competence among radiology residents, known as the RAD-Score tool, was developed by evaluating published literature and using a modified Delphi procedure involving a group of local content experts. The pilot version of the tool was tested by seven radiology department faculty members who evaluated procedures performed by 25 residents at one institution between October 2014 and June 2015. Residents were evaluated while performing multiple procedures in both clinical and simulation settings. The main outcome measure was the percentage of residents who were considered ready to perform procedures independently, with testing conducted to determine differences between levels of training., Results: A total of 105 forms (for 52 procedures performed in a clinical setting and 53 procedures performed in a simulation setting) were collected for a variety of procedures (eight vascular or interventional, 42 body, 12 musculoskeletal, 23 chest, and 20 breast procedures). A statistically significant difference was noted in the percentage of trainees who were rated as being ready to perform a procedure independently (in postgraduate year [PGY] 2, 12% of residents; in PGY3, 61%; in PGY4, 85%; and in PGY5, 88%; p < 0.05); this difference persisted in the clinical and simulation settings. User feedback and psychometric analysis were used to create a final version of the form., Conclusion: This prospective study describes the successful development of a tool for assessing the procedural competence of radiology trainees with high levels of construct validity in multiple domains. Implementation of the tool in the radiology residency curriculum is planned and can play an instrumental role in the transition to competency-based radiology training.

Inorganic nanoparticles (NPs) are studied as drug carriers, radiosensitizers and imaging agents, and characterizing nanoparticle biodistribution is essential for evaluating their efficacy and safety. Tracking NPs at the single-cell level with current technologies is complicated by the lack of reliable methods to stably label particles over extended durations in vivo. Here we demonstrate that mass cytometry by time-of-flight provides a label-free approach for inorganic nanoparticle quantitation in cells. Furthermore, mass cytometry can enumerate AuNPs with a lower detection limit of ∼10 AuNPs (3 nm core size) in a single cell with tandem multiparameter cellular phenotyping. Using the cellular distribution insights, we selected an amphiphilic surface ligand-coated AuNP that targeted myeloid dendritic cells in lymph nodes as a peptide antigen carrier, substantially increasing the efficacy of a model vaccine in a B16-OVA melanoma mouse model. This technology provides a powerful new level of insight into nanoparticle fate in vivo.

Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8 + T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.

Objective: Fat embolism syndrome (FES) is rare and diagnosis is challenging. Clinical manifestations are non-specific and no biochemical tests are reliable for diagnosis, highlighting the importance of thoracic CT. Our goal was to describe the CT manifestations of FES and assess whether imaging findings, time of onset of symptoms and time of surgery correlate with clinical course and severity of the disease., Methods: Retrospective review of 49 patients with respiratory distress after trauma/intramedullary nail fixation over a 10 year period; 12 patients met clinical criteria and were categorized as non-fulminant (NF-FES) or fulminant FES (F-FES). CT images were analyzed and electronic records reviewed for clinical findings, timeline from trauma to surgery and onset of symptoms. Pearson Chi-square and Levene's test were used and results considered significant when p<0.05., Results: All patients were men (18-80 years, mean 38 years), 5 (42%) suffered F-FES and 7 (58%) NF-FES. The most common CT finding was ground-glass opacities (8/12, 67%), often with lobular sparing. Consolidation occurred in 4/12 (33%), all in F-FES patients (p=0.004). In 5/5 F-FES, lung involvement was extensive (>75%) whereas most NF-FES had limited involvement (p<0.01). Centrilobular nodules were the predominant finding in 3/12 (16%). Median time between fracture and onset of symptoms was 43h, in 9/12 patients manifesting after surgery. Mean time between trauma and surgery was 20h in NF-FES and 52h in F-FES (p=0.02)., Conclusions: The most common CT features of FES were ground-glass opacity and consolidation, less commonly, centrilobular nodules. The extent of ground-glass opacities and the presence of consolidation correlated with disease severity. Significant difference was found from time of trauma to surgery in the two groups however is uncertain whether delayed surgery truly increased the risk of F-FES., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)