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.

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.

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.

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.

Use of Bio-integrative Screws for Fixation of Lisfranc Instability; Pros and Cons from Surgeons' Point of View in a Cadaver Study.

Objectives: Majority of Lisfranc fracture-dislocations require anatomic reduction and rigid internal fixation to prevent debilitating sequelae. Current methods include solid screws and flexible fixations which have been in use for many years. Biointegrative screw is a newer option that has not yet been thoroughly investigated for its effectiveness for Lisfranc injuries. Methods: The ligaments of the Lisfranc complex were resected in eight lower-leg cadaveric specimens. This was done by eight foot and ankle surgeons individually. Distraction forces were applied from opposite sides at the joint to replicate weight bearing conditions. Three methods of fixation - flexible fixation, metal, and biointegrative screws- were evaluated. The diastasis and area at the level of the ligament were measured at four conditions (replicated injury and each type of fixation) in neutral and distraction conditions using fluoroscopy images. The Wilcoxon test and Kruskal Wallis test were used for comparison. P value <0.05 was considered statistically significant. Results: The diastasis value for the transected ligament scenario (2.47 ± 0.51 mm) was greater than those after all three fixation methods without distraction (2.02 ± 0.5 for flexible fixation, 1.72 ± 0.63 mm for metal screw fixation and 1.67 ± 0.77 mm for biointegrative screw fixation). The transected ligament diastasis was also greater than that for metal screw (1.61 ± 1.31mm) and biointegrative screws (1.69 ± 0.64 mm) with distraction (p<0.001). The area at the level of the ligament showed higher values for transected ligament (32.7 ± 13.08 mm2) than the three fixatives (30.75 ± 7.42 mm2 for flexible fixation, 30.75 ± 17.13 mm2 for metal screw fixation and 29.53 ± 9.15 mm2 for biointegrative screw fixation; p<0.05). Conclusion: Metal screws, flexible fixation and biointegrative screws showed comparable effectiveness intra-op, in the correction of diastasis created as a consequence of Lisfranc injury.

Shoulder motion, strength, and functional outcomes in children with established malunion of the clavicle.

BACKGROUND: Recent investigations of displaced clavicle fractures in adults have demonstrated a higher prevalence of nonunion, symptomatic malunion, diminished functional outcome, and decreased strength with nonoperative treatment. Although these data have led to increased surgical management of displaced fractures, little published information is available regarding the consequences of malunion in the pediatric population. The purpose of this investigation was to assess pain, functional outcome, range of motion, and strength in children with displaced clavicle fractures treated nonoperatively. METHODS: Clinical evaluation of 16 patients with mid-diaphyseal clavicle fractures and >2 cm of initial displacement was performed; all had undergone nonoperative treatment and went on to radiographic malunion. The mean age at the time of injury was 12.2±3.3 years. Pain, aesthetic appearance, and satisfaction with treatment were rated by patients on a visual analog scale (VAS) (range 0 to 10 with 10 indicating the worst score). Patient-based outcomes were assessed with the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and the Pediatric Outcomes Data Collection Instrument (PODCI). Bilateral shoulder motion was measured by a physical therapist. Isokinetic strength testing of the bilateral shoulders was performed with a Biodex dynometer. Range of motion and strength were analyzed with a multivariable regression, controlling for hand dominance. The mean follow-up was 27.2 months after injury. RESULTS: All displaced fractures treated nonoperatively achieved union. Overall, there was reduced forward flexion and abduction on the injured side compared with the contralateral sides of 7.3 and 6.5 degrees, respectively, adjusted for hand dominance (P<0.05). Biodex testing did not detect any significant difference in abduction or adduction torque or power between affected and unaffected shoulders. The mean VAS score for pain was 1.6, with 4 patients reporting pain ≥to 3. The mean VAS scores for satisfaction with aesthetic appearance was 2.7, with 4 patients reporting scores >5. The mean VAS scores for satisfaction with treatment was 2.0, with only 1 patient scoring >5. The mean DASH score was 4.9±7.5, with 3 patients scoring ≥10. The mean scores on the DASH sports and performing arts module was 1.9±4.2, with only 1 patient scoring ≥10. The mean global PODCI score was 94.5±6.0. The mean PODCI scores for upper extremity function, sports, and pain were 97.9±5.5, 95.4±5.3, and 84.6±20.5, respectively. Only 1 patient was symptomatic enough to require corrective osteotomy. CONCLUSIONS: Skeletally immature patients with established clavicle fracture malunions do not develop clinically meaningful loss of shoulder motion or abduction/adduction strength. Routine surgical fixation for displaced, nonsegmental clavicle fractures may not be justified based upon concerns regarding shoulder motion and strength alone. Further investigation is required to determine the risk factors and causes of pain and functional compromise in the minority of pediatric patients with symptomatic malunions. LEVEL OF EVIDENCE: Level IV.

Assessing accuracy of sustentaculum screw placement during calcaneal fixation.

BACKGROUND: The aim of this study was to determine the ability of the Harris heel view to confirm placement of the sustentacular screw during calcaneal fixation. METHODS: A 4.0 cancellous screw was placed in a cadaveric specimen, from lateral to medial in 5 configurations: (1) within the sustentaculum, (2) misdirected inferiorly to sustentaculum, (3) misdirected superiorly to sustentaculum, (4) misdirected anteriorly to sustentaculum, and (5) misdirected posteriorly to sustentaculum. Harris heel views were obtained at 5 angulations and were analyzed to determine screw placement. RESULTS: A screw placed anatomically was radiographically confirmed by the Harris heel view to be within the sustentaculum in all views. An inferiorly misdirected screw appeared radiographically within the sustentaculum at 30, 40 and 50 degrees but was confirmed misplaced on the 10- and 20-degree views. A posteriorly misdirected screw was confirmed misplaced on all 5 views. An anteriorly misdirected screw appeared radiographically within the sustentaculum on the 10-degree view but was confirmed misplaced on all other views. A superiorly misdirected screw was confirmed misplaced on all views. CONCLUSIONS: Clinicians should be aware that several specific axial heel views are required to verify placement of the sustentacular screw. An inferiorly misdirected screw will appear to be within the sustentaculum with the standard Harris heel view. CLINICAL RELEVANCE: Heel views should be obtained from a range of 10 to 50 degrees to confirm accurate placement of the sustentacular screw.

Role of preoperative computed tomography scans in operative planning for malleolar ankle fractures.

BACKGROUND: There remains no consensus regarding the role of computed tomography (CT) scans in preoperative planning for malleolar ankle fractures. The aim of this study was to determine the role of preoperative CT scans on operative planning in these fractures. METHODS: A retrospective analysis was performed on 100 consecutive patients treated at our institution for malleolar ankle fractures (AO type 44) with both preoperative radiographs and CT scans. Six study participants reviewed available radiographs and formulated an operative (or nonoperative) plan including positioning, operative approach, and fixation. Participants then analyzed CT scans of the same fractures, deciding whether (and how) they would alter operative strategy. Characteristics of fractures and radiographs were correlated with changes in operative strategy. RESULTS: Operative strategy was notably changed in 24% of cases after CT review, with strong intraclass correlation (0.733). Common changes included alterations in medial malleolar (21%) or posterior malleolar (15%) fixation and fixation of an occult anterolateral plafond fracture (9%). Notable predictors of changes in operative strategy included trimalleolar over unimalleolar fractures (29% vs 10% rate of change), preoperative dislocation over no dislocation (31% vs 20%), the presence of only radiographs with overlying plaster versus fractures with at least 1 set of radiographs without plaster (25% vs 14%), and suprasyndesmotic versus trans- and infra-syndesmotic fractures (40% vs 20% and 4%, respectively). CONCLUSIONS: CT scans may be useful adjuncts in preoperative planning for malleolar ankle fractures, most notably in fracture dislocations, cases in which all available radiographs are obscured by plaster, trimalleolar fractures, and suprasyndesmotic fractures. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

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.

Does Screw Order Matter? A Technique Tip to Prevent Loss of Fracture Reduction during Surgical Fixation of Lateral Malleolus Fractures.

When obtaining surgical fixation of lateral malleolus fractures, a cortical lag screw is commonly used to obtain anatomic reduction. Subsequently, a neutralization plate is applied. Slight loss of fracture reduction after plate placement occasionally occurs. Although this is frequently attributed to poor bone quality or suboptimal initial lag screw fixation, a frequently overlooked factor is screw order when applying the neutralization plate. The purpose of this technique tip is to highlight the biomechanical rationale behind this loss of reduction and advocate a specific screw order for lateral malleolus fixation.

Lack of Surgeon Standardization on Implant Selection in Ankle Fracture Fixation May Increase Costs and Decrease Contribution Margin.

BACKGROUND: Surgical standardization has been shown to decrease costs without impacting quality; however, there is limited literature on this subject regarding ankle fracture fixation. Methods. Between October 5, 2015 and September 27, 2017, a total of 168 patients with isolated ankle fractures who underwent open reduction, internal fixation (ORIF) were analyzed. Financial data were analyzed across ankle fracture classification type, implant characteristics, and surgeons. Bivariate analyses were conducted. One-way analysis of variance was used to compare hardware costs across all 5 surgeons. Linear regression analysis was used to determine if hardware cost differed by surgeon when accounting for fracture type. RESULTS: The mean contribution margin was $4853 (SD $6446). There was a significant difference in implant costs by surgeon (range, lowest-cost surgeon: $471 [SD $283] to $1609 [SD $819]; P < .001). There was no difference in the use of a suture button or locking plate by fracture type (P = .13); however, the cost of the implant was significantly higher if a suture button or locking plate was used ($1014 [SD $666] vs $338 [SD $176]; P < .001). There was an association between surgeon 3 (ß = 200.32 [95% CI 6.18-394.47]; P = .043) and surgeon 4 (ß = 1131.07 [95% CI 906.84-1355.30]; P < .001) and higher hardware costs. CONCLUSIONS: Even for the same ankle fracture type, a wide variation in implant costs exists. The lack of standardization among surgeons accounted for a nearly 3.5-fold difference, on average, between the lowest- and highest-cost surgeons, negatively affecting contribution margin. LEVELS OF EVIDENCE: Level IV.

Relative strengths of the calf muscles based on MRI volume measurements.

BACKGROUND: In 1985, Silver et al. published a cadaver study which determined the relative order of strength of the muscles in the calf. Muscle strength, which is proportional to volume, was obtained by dissecting out the individual muscles, weighing them, and then multiplying by the specific gravity. No similar studies have been performed using {\it in vivo} measurements of muscle volume. METHODS: Ten normal subjects underwent 3-Tesla MRI's of both lower extremities using non-fat-saturated T2 SPACE sequences. The volume for each muscle was determined by tracing the muscle contour on sequential axial images and then interpolating the volume using imaging software. RESULTS: The results from this study differ from Silver's original article. The lateral head of the gastrocnemius was found to be stronger than the tibialis anterior muscle. The FHL and EDL muscles were both stronger than the peroneus longus. There was no significant difference in strength between the peroneus longus and brevis muscles. CONCLUSION: This revised order of muscle strengths in the calf based on in vivo MRI findings may assist surgeons in determining the optimal tendons to transfer in order to address muscle weakness and deformity.