Association between cervical fracture patterns and blunt cerebrovascular injury when screened with computed tomographic angiography.

BACKGROUND CONTEXT: Prior studies have demonstrated a close association between cervical spine fractures and blunt cerebrovascular injuries (BCVI). Undiagnosed BCVI is a feared complication because of the potentially catastrophic outcomes in a missed posterior circulation stroke. Computed tomography angiography (CTA) is commonly used to screen BCVI in the trauma setting. However, determining which cervical fracture patterns mandate screening is still not clearly known. PURPOSE: The aim of this retrospective review is to further elucidate which fracture patterns are associated with BCVI when using CTA and may mandate screening. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: All patients that presented to our trauma and emergency departments with a blunt cervical spine fracture from January 2018 to December 2021. Inclusion criteria included blunt cervical trauma and the use of CTA for BCVI screening. Exclusion criteria included patients under the age of 18, penetrating cervical trauma, and use any imaging modality besides CTA for BCVI screening. OUTCOME MEASURES: Patient demographics (age, gender, Glasgow coma scale, hospital length of stay (LOS), intensive care unit LOS, mechanism of energy of injury, polytrauma status), fracture location, fracture pattern (anterior arch, dens, dislocations/subluxations, facet, hangman, Jefferson, lamina, lateral mass, occipital condyle dissociation, occipital condyle, pedicle, posterior arch, spinous process, transverse process, transverse foramen, and vertebral body), and whether the patient sustained a BCVI or CVA. METHODS: If a patient had multiple fracture levels or fracture patterns, each level and pattern was counted as a separate BCVI. Multilevel fractures were defined as any patient with fractures at two distinct cervical levels. Differences between the patients who had a BCVI and those who did not were analyzed using independent sample t-tests for continuous variables and the chi-square or Fisher exact test for categorical variables. Odds ratios and 95% confidence intervals were calculated to assess likelihood between patient characteristics/fracture characteristics and BCVI. RESULTS: A total of 690 patients were identified as having a blunt cervical spine injury. A total of 453 patients (66%) underwent screening for BCVI with CTA. Among patients who underwent CTA, BCVI was diagnosed in 138 patients (30%), VAI in 119 patients (26%), CAI in 30 patients (7%), and 11 patients were diagnosed with both a VAI and CAI (2%). Overall, among all patients there were 9 strokes, all in patients identified with a BCVI (1%). No individual cervical level was associated with increased risk of BCVI, but when combined, OC-C3 fractures were associated with an increased risk (OR: 1.4, 95% CI: 1.0-1.9, p-value: .006). Multilevel fractures were also associated with an increased risk (OR: 1.7, 95% CI: 1.1-2.3, p-value: .01). The only fracture pattern associated with increased risk of BCVI were fractures associated with a dislocation/subluxation (OR: 3.8, 95% CI: 1.9-7.8, p-value = .0001). CONCLUSIONS: The only fracture pattern associated with an increased risk of BCVI were fractures associated with dislocation/subluxation. The only fracture levels associated with BCVI were combined OC-C3 and multilevel fractures. We recommend that any upper cervical fracture (OC-C3), multilevel fracture, or fracture with dislocation/subluxation undergo screening for BCVI.

Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion.

Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of murine tumors with low ITH. We compared the temporal growth of homogeneous, genetically-similar single-cell clones that are rejected vs. those that are not-rejected after transplantation in-vivo using single-cell RNA sequencing and immunophenotyping. Non-rejected clones showed high infiltration of tumor-associated-macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate mediators, identified Mif (macrophage migration inhibitory factor) as a regulator of immune rejection. Mif knockout led to smaller tumors and reversed non-rejection-associated immune composition, particularly, leading to the reduction of immunosuppressive macrophage infiltration. Finally, we validated these results in melanoma patient data.

Glioma synapses recruit mechanisms of adaptive plasticity.

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

The ageing immune system as a potential target of senolytics.

Ageing leads to a sharp decline in immune function, precipitating the development of inflammatory conditions. The combined impact of these processes renders older individuals at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This is compounded by reduced efficacy in interventions aiming to limit disease impact, for instance vaccines being less effective in elderly populations. This state of diminished cellular function is driven by cellular senescence, a process where cells undergo stable growth arrest following exposure to stressful stimuli, and the associated pro-inflammatory secretory phenotype. Removing harmful senescent cells (SnCs) using senolytic therapies is an emerging field holding promise for patient benefit. Current senolytics have been developed either to specifically target SnCs, or repurposed from cancer therapies or vaccination protocols. Herein, we discuss recent developments in senolytic therapies, focusing on how senolytics could be used to combat the age-associated diminution of the immune system. In particular, exploring how these drugs may be used to promote immunity in the elderly, and highlighting recent trials of senolytics in idiopathic pulmonary fibrosis and diabetic kidney disease. Novel immunotherapeutic approaches including chimeric antigen receptor T-cells or monoclonal antibodies targeting SnCs are being investigated to combat the shortcomings of current senolytics and their adverse effects. The flexible nature of senolytic treatment modalities and their efficacy in safely removing harmful SnCs could have great potential to promote healthy immune function in ageing populations.

Targeting TBK1 to overcome resistance to cancer immunotherapy.

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

Systematic discovery of recombinases for efficient integration of large DNA sequences into the human genome.

Large serine recombinases (LSRs) are DNA integrases that facilitate the site-specific integration of mobile genetic elements into bacterial genomes. Only a few LSRs, such as Bxb1 and PhiC31, have been characterized to date, with limited efficiency as tools for DNA integration in human cells. In this study, we developed a computational approach to identify thousands of LSRs and their DNA attachment sites, expanding known LSR diversity by >100-fold and enabling the prediction of their insertion site specificities. We tested their recombination activity in human cells, classifying them as landing pad, genome-targeting or multi-targeting LSRs. Overall, we achieved up to seven-fold higher recombination than Bxb1 and genome integration efficiencies of 40-75% with cargo sizes over 7 kb. We also demonstrate virus-free, direct integration of plasmid or amplicon libraries for improved functional genomics applications. This systematic discovery of recombinases directly from microbial sequencing data provides a resource of over 60 LSRs experimentally characterized in human cells for large-payload genome insertion without exposed DNA double-stranded breaks.

In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer.

The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1b/HLA-E. Surprisingly, loss of tumor interferon-γ (IFNγ) signaling sensitizes many models to immunity. The immune inhibitory effects of tumor IFN sensing are mediated through two mechanisms. First, tumor upregulation of classical MHC class I inhibits natural killer cells. Second, IFN-induced expression of Qa-1b inhibits CD8+ T cells via the NKG2A/CD94 receptor, which is induced by ICB. Finally, we show that strong IFN signatures are associated with poor response to ICB in individuals with renal cell carcinoma or melanoma. This study reveals that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints can facilitate immune escape.

Cervical fracture patterns associated with blunt cerebrovascular injures when utilizing computed tomographic angiography: a systematic review and meta-analysis.

BACKGROUND CONTEXT: Prior studies have demonstrated an association between cervical spine fractures and blunt cerebrovascular injuries (BCVI) due to the intimate anatomic relationship between the cervical spine and the vertebral arteries. Digital subtraction angiography (DSA) has historically been the gold standard, but computed tomography angiography (CTA) is commonly used to screen for BCVI in the trauma setting. However, there is no consensus regarding which fracture patterns mandate screening. Over aggressive screening may lead to increased radiation, increased false positives, and overtreatment of patients which can cause unnecessary patient harm, and increased healthcare costs. PURPOSE: The aim of this meta-analysis is to analyze which cervical spine fracture patterns are most predictive of BCVI when utilizing CTA. STUDY DESIGN/SETTING: Systematic review and meta-analysis. OUTCOME MEASURES: Odds ratios for specific cervical fracture patterns and risk of developing a BCVI. METHODS: A systematic literature review of all English language studies from 2000-2020 was conducted. The year 2000 was chosen as the cut-off because use of CTA prior to 2000 was rare. Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Scopus, Global Index Medicus, and ClinicalTrials.gov were queried. Studies were included if they met the following criteria: (1) the diagnostic imaging modality was CTA; (2) investigated blunt cervical trauma; (3) noted specific cervical spine fracture patterns associated with BCVI; (4) odds ratios for specific cervical spine fracture patterns or the odds ratio could be calculated; (5) subjects were 18 years old or older. Studies were excluded if they: (1) included DSA or magnetic resonance imaging; (2) included penetrating cervical trauma; (3) included pediatric patients less than 18 years of age; (4) were not written in English. All statistical analysis was performed using R Studio (RStudio, Boston, MA, USA). RESULTS: The initial search, after duplicates were removed, resulted in 10,940 articles for independent review. Six studies met the criteria for inclusion in the meta-analysis. Specific fracture patterns mentioned are isolated C1, C2, C3 fractures, any C1-C3 fracture, any C4-C7 fracture, two-level fractures, subluxation/dislocations, and transverse foramen (TF) fractures. Three studies were included in the meta-analysis for C1, C2, C1-C3, subluxations/dislocations, and TF fractures. Two studies were included in the meta-analysis for C3, C4-C7, and two-level fractures. The pooled odds ratio with 95% confidence interval for: C1 fractures and BCVI is 1.3 (0.8-2.1); C2: 1.6 (0.9-2.8); C3: 1.8 (0.9-3.6); C1-C3: 2.2 (1.1-4.2); C4-C7: 0.7 (0.3-1.7); Two-level: 2.5 (1.4-4.6); Subluxation/Dislocation: 2.9 (1.8-4.5); TF: 3.6 (1.4-8.9). DISCUSSION/CONCLUSION: This study found that when utilizing CTA for screening of BCVI only fractures in the C1-C3 region, two-level fractures, subluxations/dislocations, and transverse foramen fractures were associated with increased incidence of a BCVI. Further refinement of protocols for CTA in the setting of blunt cervical trauma may help limit unnecessary patient harm from overtreatment and reduce healthcare costs.

Checkpoint blockade-induced CD8+ T cell differentiation in head and neck cancer responders.

BACKGROUND: Immune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%-20% of patients and underpinnings of resistance remain undefined. METHODS: Starting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors. To examine heterogeneity and clonal dynamics of tumor infiltrating lymphocytes (TILs), we applied paired single-cell RNA and TCR sequencing in three HNSCC models. RESULTS: Anti-PD1 resistant MOC1esc1 line displayed a conserved cell intrinsic immune evasion signature. Immunoprofiling showed distinct baseline tumor microenvironments of MOC1 and MOC1esc1, as well as the remodeling of immune compartments on ICB in MOC1esc1 tumors. Single cell sequencing analysis identified several CD8 +TIL subsets including Tcf7 +Pd1- (naïve/memory-like), Tcf7 +Pd1+ (progenitor), and Tcf7-Pd1+ (differentiated effector). Mapping TCR shared fractions identified that successful anti-PD1 or anti-CTLA4 therapy-induced higher post-treatment T cell lineage transitions. CONCLUSIONS: These data highlight critical aspects of CD8 +TIL heterogeneity and differentiation and suggest facilitation of CD8 +TIL differentiation as a strategy to improve HNSCC ICB response.

Research Productivity of Foot and Ankle Fellowship Faculty.

BACKGROUND: Contribution to literature is critical for progress in the field of orthopaedics. No previous study has yet examined the academic productivity of foot and ankle surgery fellowship faculty. PURPOSE: To evaluate the publishing productivity of foot and ankle fellowship faculty. METHODS: Faculty and program characteristics of orthopaedic foot and ankle fellowship programs across the United States and Canada were collected from American Orthopaedic Foot and Ankle Society (AOFAS) and program websites. Faculty publication productivity measures, including publications, number of publications in specific journals, number of citations, and Hirsch index (h-index) were gathered using the Scopus database. RESULTS: A total of 48 AOFAS foot and ankle surgery fellowship programs were identified with an associated 185 faculty members. The mean number of publications per faculty member was 44.9 (SD = 53.0; range = 0-323), with a mean h-index of 11.9 (SD = 10.6; range = 0-54). A total of 144 (77.8%) academic-affiliated faculty had a significantly greater number of publications (P < .01), total citations (P < .05), and publications in Foot and Ankle International (P < .05), Journal of Bone and Joint Surgery (P < .05), Clinical Orthopaedics and Related Research (P < .05), and Journal of the American Academy of Orthopaedic Surgeons (P < .05) compared to the 41 (22.2%) nonacademic faculty. There were no significant differences between measures of publication productivity between male and female faculty, except for maximum citations in a single article (67.1 vs 142.3; P < .05). CONCLUSIONS: Academic-affiliated foot and ankle fellowship faculty have higher research productivity than nonacademic surgeons. The mean h-index of foot and ankle fellowship faculty was 11.9, which is lower than that reported in sports, joints, and spine fellowship faculty but higher than that reported for hand fellowship faculty. LEVEL OF EVIDENCE: Level IV.

Early detection of T-cell lymphoma with T follicular helper phenotype by RHOA mutation analysis.

Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma with T follicular helper phenotype (PTCL-TFH) are a group of complex clinicopathological entities that originate from T follicular helper cells and share a similar mutation profile. Their diagnosis is often a challenge, particularly at an early stage, because of a lack of specific histological and immunophenotypic features, paucity of neoplastic T cells and prominent polymorphous infiltrate. We investigated whether the lymphoma-associated RHOA Gly17Val (c.50G>T) mutation, occurring in 60% of cases, is present in the early "reactive" lesions, and whether mutation analysis could help to advance the early diagnosis of lymphoma. The RHOA mutation was detected by quantitative polymerase chain reaction with a locked nucleic acid probe specific to the mutation, and a further peptide nucleic acid clamp oligonucleotide to suppress the amplification of the wild-type allele. The quantitative polymerase chain reaction assay was highly sensitive and specific, detecting RHOA Gly17Val at an allele frequency of 0.03%, but not other changes in Gly17, nor in 61 controls. Among the 37 cases of AITL and PTCL-TFH investigated, RHOA Gly17Val was detected in 62.2% (23/37) of which 19 had multiple biopsies including preceding biopsies in ten and follow-up biopsies in 11 cases. RHOA Gly17Val was present in each of these preceding or follow-up biopsies including 18 specimens that showed no evidence of lymphoma by combined histological, immunophenotypic and clonality analyses. The mutation was seen in biopsies 0-26.5 months (mean 7.87 months) prior to the lymphoma diagnosis. Our results show that RHOA Gly17Val mutation analysis is valuable in the early detection of AITL and PTCL-TFH.

Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.

Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.

In vivo screens using a selective CRISPR antigen removal lentiviral vector system reveal immune dependencies in renal cell carcinoma.

CRISPR-Cas9 genome engineering has increased the pace of discovery for immunology and cancer biology, revealing potential therapeutic targets and providing insight into mechanisms underlying resistance to immunotherapy. However, endogenous immune recognition of Cas9 has limited the applicability of CRISPR technologies in vivo. Here, we characterized immune responses against Cas9 and other expressed CRISPR vector components that cause antigen-specific tumor rejection in several mouse cancer models. To avoid unwanted immune recognition, we designed a lentiviral vector system that allowed selective CRISPR antigen removal (SCAR) from tumor cells. The SCAR system reversed immune-mediated rejection of CRISPR-modified tumor cells in vivo and enabled high-throughput genetic screens in previously intractable models. A pooled in vivo screen using SCAR in a CRISPR-antigen-sensitive renal cell carcinoma revealed resistance pathways associated with autophagy and major histocompatibility complex class I (MHC class I) expression. Thus, SCAR presents a resource that enables CRISPR-based studies of tumor-immune interactions and prevents unwanted immune recognition of genetically engineered cells, with implications for clinical applications.

Changes in knee kinematics from applied external Tibial torque: Implications for stabilizing an anterior cruciate ligament deficient knee.

BACKGROUND: Changes in knee kinematics from internal tibial torque under tibiofemoral compression force have been studied, but the potentially stabilizing effects of external tibial torque have not been reported. We hypothesized that for a given knee flexion angle, 1) external torque would significantly reduce anterior tibial translation, internal tibial rotation, and valgus tibial rotation before and after sectioning the anterior cruciate ligament and 2) changes in kinematics from applied external torque would be significantly greater with the cruciate cut. METHODS: A robotic test system was used to flex intact human knees continuously from 0° to 50° under 200 N compression, without and with 5 Nm external torque. Tests were repeated after cruciate section. FINDINGS: With the cruciate intact, external torque had no significant effect on anterior translation, and significantly reduced internal and valgus rotations at all flexion angles. With the cruciate cut, external torque significantly reduced anterior translation beyond 25° flexion, significantly reduced internal rotation at all flexion angles, and significantly reduced valgus rotation beyond 15° flexion. Although external torque had no significant effect on anterior translation with the ACL intact, external torque produced relatively large decreases in anterior translation with the cruciate sectioned (-11.6 mm at 50° flexion). Reductions in valgus rotation from applied external torque were significantly greater for cruciate deficient knees beyond 25° flexion. INTERPRETATION: We conclude that external tibial torque may be important for controlling the abnormal kinematics associated with an anterior cruciate ligament deficient knee, and possibly help stabilize the knee during in vivo activities.

Website evaluation for shoulder and elbow fellowships in the United States: an evaluation of accessibility and content.

HYPOTHESIS AND/OR BACKGROUND: When examining the access and content related to shoulder and elbow fellowship websites, only 64% of programs had individual websites in a query performed 5 years earlier. The purpose of this study was to re-evaluate content about individual programs listed on the American Shoulder and Elbow Surgeons (ASES) website and on individual program websites and compare the results to prior data. METHODS: The ASES website was accessed to determine both the number of ASES-recognized shoulder and elbow fellowships and the number of direct links to fellowship program websites. A Google search was also performed to determine the ease of access to fellowship program websites. Each website was then evaluated for content in regard to their recruitment and educational program. RESULTS: The ASES website includes contact information and a brief description for 29 programs with 40 reported positions. When trying to identify links to program websites, there were functioning links to 6 programs (21%) and absent/nonfunctioning links for the remaining 23 (79%). Through a Google search, there were functioning links to 22 (76%) and absent/nonfunctioning links for 7 (24%) programs. All 29 program websites had faculty listing and program contact info whereas 28 (97%) had a description of their program. In terms of educational content, 17 (59%) included description of operative cases and 18 (62%) had descriptions of rotations/curriculum. DISCUSSION AND/OR CONCLUSION: Individual shoulder and elbow fellowship program websites provide varied content and accessibility. In the intervening 5 years, there has been minimal improvement in the accessibility of individual fellowship websites from the ASES website.

An Update on Foot and Ankle Fellowship Website Content and Accessibility.

BACKGROUND: The content and accessibility of foot and ankle fellowship websites impact applicants and fellowship programs. This study aimed to evaluate the accessibility provided via the American Orthopaedic Foot & Ankle Society (AOFAS) websites and individual websites. METHODS: The AOFAS website was used to identify existing foot and ankle fellowship programs. The database information was reviewed for links to fellowship program websites, which was corroborated through a Google search for accessibility. Information from fellowship program websites and the AOFAS was analyzed for the presence of recruitment and educational content, and this analysis was compared to previously reported metrics. RESULTS: Forty-eight orthopedic foot and ankle fellowship programs were identified. The AOFAS database featured direct links to 19 (40%) fellowship websites with the Google search providing direct links to 35 (73%) websites. Foot and ankle fellowship information markedly improved in domains of Salary/Benefits (+233%), Rotations/Curriculum (+199%), and Faculty Listing (+67%), but there was a reduction in available content in the domains of Operative Experience (-79%), Office/Clinic information (-78%), and Didactics (-39%) compared with the lone existing study. CONCLUSION: There continues to be variability between foot and ankle fellowship websites and the AOFAS website regarding program content and descriptions. Some information is more readily available, but other domains have less information now than in previously reported research.

Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade.

Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.

Femoral Contact Forces in the Anterior Cruciate Ligament Deficient Knee: A Robotic Study.

PURPOSE: To measure contact forces (CFs) at standardized locations representative of clinical articular cartilage defects on the medial and lateral femoral condyles during robotic tests with simulated weightbearing knee flexion. METHODS: Eleven human knees had 20-mm-diameter cylinders of native bone/cartilage cored from both femoral condyles at standardized locations, with each cylinder attached to a custom-built load cell that maintained the plug in its precise anatomic position. A robotic test system was used to flex the knee from 0° to 50° under 200-N tibiofemoral compression without and with a 2 Nm internal tibial torque, 5 Nm external tibial torque, and 45 N anterior tibial force (AF). CFs and knee kinematics were recorded before and after cutting the anterior cruciate ligament (ACL). RESULTS: ACL sectioning did not significantly increase medial or lateral CFs for any loading condition, with the exception of AF, in which increases in medial CF ranged from 38 N (at 15° flexion, P < .01) to 77 N (at 50° flexion, P < .002). Compared with the intact condition, ACL sectioning significantly increased anterior tibial translation by 12.33 mm (at 15° flexion, P < .001) and 17.4 mm (at 50° flexion, P < .001), and increased valgus rotation by 2.4° (at 15° flexion, P < .001) and 3.8° (at 50° flexion, P < .001). CONCLUSIONS: Our hypothesis that CF would increase after ACL section was confirmed for the AF test condition only, and only for the medial condyle beyond 10° flexion. With the ACL sectioned, it appeared that the increased CF was owing to the medial condyle riding up over the posterior tibial plateau resulting from the large anterior tibial displacements. CLINICAL RELEVANCE: Aside from our limited finding with AF, we concluded that CFs were generally unaffected by ACL section.

Contact force between the tibial spine and medial femoral condyle: A biomechanical study.

BACKGROUND: Contact between the tibial spine and medial femoral condyle with internal tibial rotation (ITR) has been proposed as a factor for the development of osteochondritis dissecans lesions. We hypothesized that tibial spine contact force (CF) would increase significantly with applied internal tibial torque (IT). METHODS: A 20 mm diameter cylinder of bone encompassing the tibial spine was cored and attached to a load cell. The isolated bone cylinder included the tibial attachments of the anterior cruciate ligament (ACL) and anterior horn of the lateral meniscus (AHLM). Eleven human cadaveric knees were flexed from 0°-50° under 200 N of tibiofemoral compression (TFC), without and with 2 N-m IT. Tests were repeated with the AHLM cut, and again with both AHLM and ACL cut, where the load cell recorded CF alone without contributions from any ligamentous attachments. FINDINGS: There were no significant differences in CF, ITR, or valgus tibial rotation (VTR) after sectioning the AHLM, without or with applied IT. With no tibial torque, mean CFs were less than 20 N throughout the flexion range. Addition of IT significantly increased 1) mean CF by 44.4 N(SD 15.8 N) at 0°(+240%) and 27.2 N(SD 5.0 N) at 20°(+675%), 2), mean ITR by 10.2°(SD 0.8°) at 0° flexion and 18.6°(SD 2.0°) at 20° flexion, and 3) mean VTR by 1.3°(SD 0.4°) at 0° flexion and 4.4°(SD 0.8°) at 20° flexion. INTERPRETATION: Our hypothesis was confirmed only between 0° and 20° of knee flexion, where the intercondylar separation distance is relatively small and the possibility of tibial spine contact with ITR is greater.