A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.

Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8(+) tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8(+) TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact.

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease.

OBJECTIVES: Primary nonresponse (PNR) to antitumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR. PATIENTS AND METHODS: Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide association study (PheWAS). RESULTS: We identified rs34767465 as associated with PNR to anti-TNFα therapy (odds ratio: 2.07, 95% CI, 1.46-2.94, P = 2.43 × 10-7, [replication odds ratio: 1.8, 95% CI, 1.04-3.16, P = 0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNFα secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy-related pathway genes suggesting autophagy-mediated TNFα secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [P = 3.7 × 10-4], pigmentary iris degeneration [P = 5.9 × 10-4], diverticulum of esophagus [P = 7 × 10-4]). CONCLUSIONS: We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD.

Effect of Bone Quality and Leg Depth on the Biomechanical Performance of a Nitinol Staple.

The use of Nitinol compression staples has increased in foot and ankle procedures due to their ease of delivery and ability to offer sustained, dynamic compression. Prior biomechanical studies have predominantly examined mechanical performance in healthy bone models without investigating the effect of unicortical versus bicortical fixation. The purpose of this study was to examine the effect of bone quality and staple leg depth on the biomechanical performance of Nitinol staples in a bicortical bone model. Two-legged Nitinol staples were implanted in bicortical sawbone of 2 densities. Two different leg depths were tested to simulate unicortical versus bicortical fixation. Interfacial compressive forces, interfacial compression area, torsional strength, and shear strength were measured for each group. The effect of leg depth was minimal compared to the effect of sawbone density on the mechanical performance of Nitinol staples. Interfacial compressive force and interfacial compression areas were greater in the low density bone model, while torsional strength and shear strength were greater in the normal density bone model. Nitinol staple's mechanical performance is highly dependent upon bone quality and less dependent on whether staple legs terminate in cancellous versus cortical bone. Low density bone allows for a higher compressive interfacial area to be imparted by the staple. Staples in normal density bone are able to resist torsion and shear deformation more readily than staples in low density bone. Bone density may have a greater effect on the Nitinol staple's stability and compressive capability in vivo as compared to unicortical versus bicortical leg fixation.

Patient Perception and Clinical Impact of Direct-to-Consumer Advertising in Inflammatory Bowel Disease.

INTRODUCTION: With an increasing number of available therapies for inflammatory bowel disease (IBD), little is known about patients' attitudes regarding IBD-related direct-to-consumer advertising (IBD-DTCA) and its impact on treatment decisions in clinical practice. METHODS: We administered a 58-item, mailed questionnaire to patients with IBD receiving Gastroenterology subspecialty care at a large academic health system. The survey assessed patient awareness and perception of IBD-DTCA and its effect on IBD treatment discussions and decisions. We used bivariate analysis to evaluate patient-level factors associated with awareness and favorable perception of IBD-DTCA. RESULTS: We achieved a response rate of 15.2% (n = 226 of 1486). Most patients (93.3%) reported awareness of IBD-DTCA, with adalimumab receiving the most exposure. A majority of respondents reported IBD-DTCA made them more aware of treatments they otherwise would not know about (53.6%), provided information in a balanced manner (63.5%), and taught them about new potential risks and side effects (64.5%). Patients without a college degree and those with a household income less than $75 k per year perceived IBD-DTCA more favorably. However, IBD-DTCA rarely changed IBD management, with only 7.6% of respondents having a discussion with their provider about the advertised drug and only two (0.9%) being initiated on the advertised drug. CONCLUSION: IBD patients were aware of IBD-DTCA and perceived it favorably; however, IBD-DTCA rarely led to patient-provider discussions or changes in treatment regimen.

Anatomic reconstruction of the medial collateral ligament in multi-ligaments knee injury using achilles allograft : a modification of Marx's technique.

Medial Collateral Ligament (MCL) injury may require operative treatment. Marx et al. described the latest technique for reconstruction of MCL. While good results have been reported using the Marx technique, some issues have been observed. To address the mentioned issues, a modification to the Marx technique has been devised. Eleven patients were enrolled and their ligaments were repaired by the fixation of allograft on the proximal and distal attachment footprints of the superficial MCL. For preventing loss of knee ROM, MCL and other ligaments were reconstructed in 2 separate stages. At the last follow up the ROM, knee ligament laxity and functional outcome scores, subjective (IKDC) and Lysholm score were evaluated and recorded. Knee motion was maintained in all cases. Two cases demonstrated 1+ valgus instability at 30 degrees of knee flexion. Both were treated for combined MCL and PCL tear, the rest were stable. The average IKDC-subjective score was 93 ± 4 and the average Lysholm score was 92 ± 3. All patients were satisfied and returned to their previous level of activity. In this technique, the superficial MCL was recon- structed closer to its anatomical construct. Patients didn't have any complaints of hardware under the skin and the need for a second surgery for hardware removal was avoided. Patients didn't have any complaints of hardware under the skin and the need for a second surgery for hardware removal was avoided. Also reconstructing the ligaments in 2 stages helped to preserve the knee motion. Level of Evidence : Level IV therapeutic.

The Ischemic toe following forefoot surgery: A review of current practices and a proposed approach for management.

Toe hypoperfusion is a commonly encountered concern following forefoot surgery, yet there is limited clinical guidance available to surgeons to aid in management of this scenario. This work aims to review the etiology, pathophysiology and current strategies to address a perioperative ischemic toe. The authors review various interventions to approach this problem based on available evidence and clinical experience. Interventions to restore perfusion can be loosely based on the ischemic causality they intend to address. Described maneuvers to restore perfusion have, in turn, been designed to either chemically (through topical/local medication) or mechanically (bending/removing K-wires, adjusting repair tension) aid in mitigation of the offending cause. Depending upon the type of surgery performed, which may or may not include instrumentation, a surgeon can implement a series of steps to maximize restoration of toe perfusion. LEVEL OF EVIDENCE: V.

Assessment of variables that influence agreement between reviewers for Foot & Ankle International.

INTRODUCTION: A common criticism of the peer-review process is the often disparate nature of reviewer recommendations when a decision is rendered which belies the supposed uniformity of the process. The purpose of this investigation was to examine level of agreement between reviewers for Foot & Ankle International (FAI) and analyze variables which may have influenced agreement in order to better understand the peer-review process. METHODS: Approval to conduct this investigation was obtained from the Executive Board and Editor in Chief of FAI. All manuscripts submitted to FAI during the calendar year 2016 which underwent formal peer-review were included in the analysis. For each reviewed manuscript, demographic data was collected regarding specific reviewer and manuscript characteristics in a de-identified manner. RESULTS: 442 manuscripts underwent formal blinded peer-review by two independent reviewers during the study period. Only 199 manuscripts (45%) had a decision rendered in which both reviewers agreed on the same initial recommendation. There were no differences in demographic characteristics between the group of reviewers who agreed as compared to those who disagreed on the initial round of peer review. A similar number of indexed peer-reviewed publications between reviewers correlated with increased levels of agreement. CONCLUSIONS: During the study period, there was 45% initial agreement between reviewers for FAI when assessing the same manuscript. Aside from research productivity, no other reviewer-specific variables examined in this investigation were found to correlate with agreement. Specific recommendations and changes may be considered to increase the efficiency and effectiveness of the peer-review process.

Trends in Foot and Ankle Studies Published in High-Impact General Medical Journals: A Systematic Review.

The foot and ankle surgery literature lacks an analysis of studies published in general medical journals. Studies published in general medical journals have high visibility and significant impact on decision making by medical practitioners and health care policy makers. Knowledge of the subject matter and methodologic characteristics of foot and ankle publications being read by general medical practitioners and the lay public is important to the practicing foot and ankle surgeon. A systematic review of foot and ankle studies published from 2000 to 2017 in 5 high-impact general medical journals was undertaken. Data extracted included study topic, study design, study demographics, and methodologic characteristics of randomized controlled trials (RCTs). There were 47 foot and ankle studies published in the selected medical journals examined during the study time period. Most common topics were diabetic foot ulcers (n = 25 [53.2%]), plantar fasciitis (n = 6 [12.8%]), and Achilles tendinopathy (n = 5 [10.6%]). The most common study types were reviews (n = 24 [51.1%]), RCTs (n = 12 [25.4%], and prospective studies (n = 6 [12.8%]). Of the published RCTs, the most common journal of publication was the Journal of the American Medical Association (n = 7 [58.3%]). The median number of citations for RCTs published before 2016 was 242.5. Of the small number of RCTs that compared operative with nonoperative treatment, the majority supported nonoperative management (n = 3 [75%]). Diabetic foot ulcers, plantar fasciitis, and Achilles tendinopathy are the most commonly published foot and ankle topics in general medical journals.

Complete Cuboid Dislocation With Associated Lisfranc Injury: A Case Report and Review of the Literature.

Cuboid dislocations are rare midfoot injuries that usually occur in the setting of high-energy trauma. Diagnosis can be challenging and optimal treatment remains unknown. This case report and review aims to summarize the recent literature on this topic.

Tibiotalocalcaneal Arthrodesis Utilizing a Titanium Intramedullary Nail With an Internal Pseudoelastic Nitinol Compression Element: A Retrospective Case Series of 33 Patients.

Nitinol has been shown to generate durable compression under loading via pseudoelastic shape memory. The purpose of this study was to evaluate the effectiveness of a hindfoot arthrodesis nail with an internal pseudoelastic nitinol compression element. Patients who had undergone tibiotalocalcaneal arthrodesis from 2013 to 2016 were identified at 2 tertiary referral centers (12-week follow-up minimum). Patients managed with a tibiotalocalcaneal nail with an internal nitinol compression element were identified for review. Sagittal computed tomographic scan reformats were reviewed to calculate a percentage of joint surface bony union. Intraoperative and postoperative radiographs were compared to calculate postoperative screw position change generated by the nitinol element, a surrogate for postoperative unloading of compressive forces. Thirty-three patients were included in analysis and 81% of patients had successful union of both tibiotalar and subtalar joints. Overall, 90% of all arthrodesis surfaces united. The union rate of arthrodesis surfaces among patients without Charcot osteoarthropathy was 94%. A history of Charcot was identified as a risk factor for subtalar nonunion (p = .04) and was associated with less complete computed tomography-based tibiotalar union: 94% versus 71% (p < .01). The posterior-to-anterior screw translated an average of 3.9 mm proximally relative to the rigid portion of the nail from intraoperative to initial postoperative radiographs (p < .0001). High rates of computed tomography-confirmed union were demonstrated in the face of challenging clinical scenarios. Shortening of the pseudoelastic nitinol element occurs early in the postoperative period, indicating continued unloading of the nitinol compression element through the arthrodesis sites after initial implantation.

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

Variation in treatment of patients with inflammatory bowel diseases at major referral centers in the United States.

We performed a prospective study of patients with inflammatory bowel diseases to examine variations in treatment among medical centers. In a prospective cohort study of 1659 patients with Crohn's disease and 946 patients with ulcerative colitis seen at 7 high-volume referral centers, we collected data on demographics, disease characteristics, and medical and surgical treatments. We used logistic regression to determine differences in treatment among centers, controlling for potential confounders. We found significant variations among centers in the treatment of Crohn's disease with immunomodulators (odds ratio [OR], 3.34; 95% confidence interval [CI], 2.09-5.32) but not anti-tumor necrosis factor agents (OR, 1.64; 95% CI, 0.97-2.77). There was less variation in the treatment of ulcerative colitis; we found no difference in use of immunomodulators (OR, 1.83; 95% CI, 1.00-3.36) or anti-tumor necrosis factor therapy (OR, 0.81; 95% CI, 0.40-1.65). The development and implementation of evidence-based standards of care for inflammatory bowel disease may help reduce variation and improve outcomes.

Translational repression of SLC26A3 by miR-494 in intestinal epithelial cells.

SLC26A3 [downregulated in adenoma (DRA)] is a Cl(-)/HCO3(-) exchanger involved in electroneutral NaCl absorption in the mammalian intestine. Altered DRA expression levels are associated with infectious and inflammatory diarrheal diseases. Therefore, it is critical to understand the regulation of DRA expression. MicroRNAs (miRNAs) are endogenous, small RNAs that regulate protein expression via blocking the translation and/or promoting mRNA degradation. To investigate potential modulation of DRA expression by miRNA, five different in silico algorithms were used to predict the miRNAs that target DRA. Of these miRNAs, miR-494 was shown to have a highly conserved putative binding site in the DRA 3'-untranslated region (3'-UTR) compared with other DRA-targeting miRNAs in vertebrates. Transfection with pmirGLO dual luciferase vector containing DRA 3'-UTR (pmirGLO-3'-UTR DRA) resulted in a significant decrease in relative luciferase activity compared with empty vector. Cotransfection of the DRA 3'-UTR luciferase vector with a miR-494 mimic further decreased luciferase activity compared with cells transfected with negative control. The transfection of a miR-494 mimic into Caco-2 and T-84 cells significantly increased the expression of miR-494 and concomitantly decreased the DRA protein expression. Mutation of the seed sequences for miR-494 in 3'-UTR of DRA abrogated the effect of miR-494 on 3'-UTR. These data demonstrate a novel regulatory mechanism of DRA expression via miR-494 and indicate that targeting this microRNA may serve to be a potential therapeutic strategy for diarrheal diseases.

Modified free radial forearm fascia flap reconstruction of lower extremity and foot wounds: optimal contour and minimal donor-site morbidity.

BACKGROUND: Free tissue transfer is commonly required for reconstruction of distal third lower extremity injuries. Injuries involving the dorsal surface of the foot require thin pliable flaps. Musculocutaneous flaps are often too bulky to accommodate shoewear. Fasciocutaneous flaps, while an improvement, need secondary contouring procedures. The modified radial forearm fascial flap (MRFFF) may offer an alternative. METHODS: Twelve patients with distal third lower extremity wounds were reconstructed with MRFFF + split thickness skin graft. The modification in flap design leaves fascia radial to the pedicle unharvested, preserving sensibility of the dorsoradial aspect of the hand. Flaps were covered with a skin graft after inset. Donor sites were closed primarily. RESULTS: Nine wounds were traumatic-five with exposed hardware, one burn, one diabetic ulcer, and one wound dehiscence following sarcoma resection + radiation. Out of 12, 11 limbs were salvaged at 1 to 2 years follow-up. All patients ambulated on the reconstructed leg and wore a shoe comfortably. Average time to weight bearing was 2 months. The donor site was limited to 25-cm scar on the volar forearm. No persistent motor/sensory deficits occurred in donor arms. CONCLUSION: MRFFF is an excellent flap for reconstruction of the distal lower extremity. Flap contour allows excellent shoe-fitting without secondary revisions. Replacement of the adipocutaneous flap on MRFFF donor site eliminates the need for a conspicuous donor-site skin graft. The ulnar orientation of the harvested fascia prevents sensory loss in the dorsal hand. The MRFFF provides the ideal replacement of "like with like" for selected distal lower extremity wounds.

The Emerging Role of Automation, Measurement Standardization, and Artificial Intelligence in Foot and Ankle Imaging: An Update.

In the past few years, advances in clinical imaging in the realm of foot and ankle have been consequential and game changing. Improvements in the hardware aspects, together with the development of computer-assisted interpretation and intervention tools, have led to a noticeable improvement in the quality of health care for foot and ankle patients. Focusing on the mainstay imaging tools, including radiographs, computed tomography scans, and ultrasound, in this review study, the authors explored the literature for reports on the new achievements in improving the quality, accuracy, accessibility, and affordability of clinical imaging in foot and ankle.

The Influence of Talar Displacement on Articular Contact Mechanics: A 3D Finite Element Analysis Study Using Weightbearing Computed Tomography.

BACKGROUND: Talar displacement is considered the main predictive factor for poor outcomes and the development of post-traumatic osteoarthritis after ankle fractures. Isolated lateral talar translation, as previously studied by Ramsey and Hamilton using carbon powder imprinting, does not fully replicate the multidirectional joint subluxations seen in ankle fractures. The purpose of this study was to analyze the influence of multiple uniplanar talar displacements on tibiotalar contact mechanics utilizing weightbearing computed tomography (WBCT) and finite element analysis (FEA). METHODS: Nineteen subjects (mean age = 37.6 years) with no history of ankle surgery or injury having undergone WBCT arthrogram (n = 1) and WBCT without arthrogram (n = 18) were included. Segmentation of the WBCT images into 3D simulated models of bone and cartilage was performed. Three-dimensional (3D) multiple uniplanar talar displacements were simulated to investigate the respective influence of various uniaxial displacements (including lateral translation, anteroposterior translation, varus-valgus angulation, and external rotation) on the tibiotalar contact mechanics using FEA. Tibiotalar peak contact stress and contact area were modeled for each displacement and its gradations. RESULTS: Our modeling demonstrated that peak contact stress of the talus and tibia increased, whereas contact area decreased, with incremental displacement in all tested directions. Contact stress maps of the talus and tibia were computed for each displacement demonstrating unique patterns of pressure derangement. One millimeter of lateral translation resulted in 14% increase of peak talar contact pressure and a 3% decrease in contact area. CONCLUSION: Our model predicted that with lateral talar translation, there is less noticeable change in tibiotalar contact area compared with prior studies whereas external rotation greater than 12 degrees had the largest effect on peak contact stress predictions. LEVEL OF EVIDENCE: Level V, computational simulation study.