Arthroscopy Association of Canada Position Statement on Opioid Prescription After Arthroscopic Surgery.

Background: Despite the ongoing opioid epidemic, most patients are still prescribed a significant number of opioid medications for pain management after arthroscopic surgery. There is a need for consensus among orthopaedic surgeons and solutions to aid providers in analgesic strategies that reduce the use of opioid pain medications. Purpose: This position statement was developed with a comprehensive systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to synthesize the best available evidence for managing acute postoperative pain after arthroscopic surgery. Study Design: Position statement. Methods: The Embase, MEDLINE, PubMed, Scopus, and Web of Science databases were searched from inception until August 10, 2022. Keywords included arthroscopy, opioids, analgesia, and pain, and associated variations. We included exclusively RCTs on adult patients to gather the best available evidence for managing acute postoperative pain after arthroscopic surgery. Patient characteristics, pain, and opioid data were extracted, data were analyzed, and trial bias was evaluated. Results: A total of 21 RCTs were identified related to the prescription of opioid-sparing pain medication after arthroscopic surgery. The following recommendations regarding noninvasive, postoperative pain management strategies were made: (1) multimodal oral nonopioid analgesic regimens-including at least 1 of acetaminophen-a nonsteroidal anti-inflammatory drug-can significantly reduce opioid consumption with no change in pain scores; (2) cryotherapy is likely to help with pain management, although the evidence on the optimal method of application (continuous-flow vs ice pack application) is unclear; (3) and (4) limited RCT evidence supports the efficacy of transcutaneous electrical nerve stimulation and relaxation exercises in reducing opioid consumption after arthroscopy; and (5) limited RCT evidence exists against the efficacy of transdermal lidocaine patches in reducing opioid consumption. Conclusion: A range of nonopioid strategies exist that can reduce postarthroscopic procedural opioid consumption with equivalent vocal pain outcomes. Optimal strategies include multimodal analgesia with education and restricted/reduced opioid prescription.

Cutting Edge: Aire Is a Coactivator of the Vitamin D Receptor.

Vitamin D deficiency is associated with the development of autoimmunity, which arises from defects in T cell tolerance to self-antigens. Interactions of developing T cells with medullary thymic epithelial cells, which express tissue-restricted Ags, are essential for the establishment of central tolerance. However, vitamin D signaling in the thymus is poorly characterized. We find that stromal and hematopoietic cells in the mouse thymus express the vitamin D receptor (Vdr) and Cyp27b1, the enzyme that produces hormonal 1,25-dihydroxyvitamin D (1,25D). Treatment of cultured thymic slices with 1,25D enhances expression of the critical medullary thymic epithelial cell transcription factor autoimmune regulator (Aire), its colocalization with the Vdr, and enhances tissue-restricted Ag gene expression. Moreover, the Vdr interacts with Aire in a 1,25D-dependent manner and recruits Aire to DNA at vitamin D response elements, where it acts as a Vdr coactivator. These data link vitamin D signaling directly to critical transcriptional events necessary for central tolerance.

Low rates of serious complications after open Latarjet procedure at short-term follow-up.

PURPOSE: To report on intraoperative and short-term postoperative adverse events after open Latarjet procedure in patients with recurrent anterior shoulder instability. These complications were classified into different grades of severity based on the treatment required and the learning curve of the procedure. METHODS: Ninety-six patients (102 shoulders) underwent open Latarjet procedure for recurrent post-traumatic anterior glenohumeral instability between 2012 and 2020. The minimum duration of patients' follow-up was 6 months. Adverse events were classified into 3 classes based on the severity and subsequent treatment. The complications in the first 50% of all cases were compared with the latter 50% to evaluate the role of learning curve on the complication rates. RESULTS: The mean follow-up was 7.2 ± 2.8 months. The patients' mean age was 26.7 ± 8.9 years and consisted of 83 (86.4%) male and 13 (13.6%) female patients. The total adverse events rate was 18.6%. Adverse events requiring no additional treatment (class 1) occurred in 6 cases (5.8%) including fibrous union (3.9%) and asymptomatic resorption of the graft (1.9%). Adverse events requiring additional or extended nonoperative management (class 2) occurred in 8 cases (7.8%), including coracoid fracture (2.9%), musculocutaneous nerve palsy (1.9%), axillary nerve palsy (0.9%), suprascapular nerve palsy (0.9%), and stiffness (0.9%). All the nerve palsies recovered without long-term sequelae. Adverse events requiring secondary operative procedures (class 3) occurred in 5 cases (4.9%), including symptomatic hardware (1.9%), medial healing of the graft (0.9%), screw loosening (0.9%), and deep infection (0.9%). The rate of adverse events in revision cases was higher than primary cases in 11.7% and 6.8%, respectively (P = .119). The complication rate was significantly higher in the first half of the surgeons' practice (14.7%) than in the second half (3.9%) (P ≤ .05). CONCLUSIONS: The overall complication rate reported in this open Latarjet series is 18.6%; however, the rate of class 3 adverse events that required additional surgery or long-term medical treatment was only 4.9%. Revision cases had a higher rate of complications than primary cases, and the learning curve has had a significant impact on the rate of adverse events.

Active Retrieval Improves Procedural Learning in Orthopedic Surgery.

OBJECTIVE: Tests are shown to enhance learning: this is known as the "testing effect". The benefit of testing is theorized to be through "active retrieval", which is the effortful process of recalling stored knowledge. This differs from "passive studying", such as reading, which is a low effort process relying on recognition. The testing effect is commonly studied in random word list scenarios and is thought to disappear as complexity of material increases. Little is known about the testing effect in complex situations such as procedural learning. Therefore, we investigated if testing improves procedural learning of fracture fixation as compared to "passive studying". DESIGN, SETTING, AND PARTICIPANTS: Fifty participants watched an instructional video of an open reduction internal fixation of a Sawbones™ femur. Participants then performed the procedure under guided supervision (pretest). After randomization, they either read the steps (passive studying group), or wrote down the steps from memory (active retrieval group) for a period of 15 minutes. After a washout period, all participants performed the procedure without guidance (posttest) and then once more, 1 week after the initial testing (retention test). The participants were assessed using the Objective Structured Assessment of Technical Skill. Each performance was video recorded for data analysis purposes. RESULTS: Participants in the passive studying group had significantly higher Objective Structured Assessment of Technical Skill scores during immediate assessment compared to the active retrieval group (p = 0.001), especially with respect to remembering the correct order of the steps (p = 0.002). The percentage of information forgotten was significantly less in the active retrieval group (p = 0.02) at the retention test. CONCLUSION: We demonstrated that, compared to passive studying, testing with active retrieval through writing resulted in better retention of fracture fixation knowledge (i.e., less forgetting). These findings can easily be applied and incorporated in existing curricula. Future studies are needed to determine the effects of different kinds of active retrieval methods such as verbal retrieval (e.g., dictating) in surgical practice.

Arthroscopic Versus Mini-open Rotator Cuff Repair: A Randomized Trial and Meta-analysis.

BACKGROUND: Patients with complete rotator cuff tears who fail a course of nonoperative therapy can benefit from surgical repair. PURPOSE: This randomized trial compared mini-open (MO) versus all-arthroscopic (AA) rotator cuff repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients with rotator cuff tears were randomized to undergo MO or AA repair at 9 centers by 23 surgeons. The primary outcome (Western Ontario Rotator Cuff Index [WORC]) and secondary outcomes (American Shoulder and Elbow Surgeons [ASES] score, Shoulder Pain and Disability Index [SPADI] pain subscale, 12-Item Short Form Health Survey [SF-12], reported medication use, adverse events), as well as measurements of range of motion and strength, were collected at 1 month before surgery; at 2 and 6 weeks postoperatively; and at 3, 6, 12, 18, and 24 months postoperatively. A blinded radiologist evaluated rotator cuff integrity on magnetic resonance imaging (MRI) at baseline and 1 year. Intention-to-treat analysis of covariance with the preoperative WORC score, age, and tear size as covariates assessed continuous outcomes. Sex differences were assessed. A meta-analysis synthesized the primary outcome between MO and AA repair with previous trials. RESULTS: From 954 patients screened, 411 were ineligible (276 because of recovery with physical therapy), 449 were screened at surgery (175 ineligible), and 274 completed follow-up (138 MO and 136 AA). The AA and MO groups were similar before surgery. WORC scores improved from 40 preoperatively to 89 (AA) and 93 (MO) at 2 years, for an adjusted mean difference of 3.4 (95% CI, -0.4 to 7.2). There were no statistically significant differences between the AA and MO groups at any time point. All secondary patient-reported outcomes were not significantly different between the MO and AA groups, except the 2-year SPADI pain score (8 vs 12, respectively; P = .02). A similar recovery in range of motion and strength occurred in both groups over time. MRI indicated minimal improvement in muscle relative to fat (AA: n = 3; MO: n = 2), with most worsening (AA: n = 25; MO: n = 24) or remaining unchanged (AA: n = 70; MO: n = 70). Opioid use was significantly reduced after surgery (from 21% to 5%). The meta-analysis indicated no significant standardized mean difference between groups in the primary outcome across all pooled studies (standardized mean difference, -0.06 [95% CI, -0.34 to 0.22]). CONCLUSION: Both AA and MO rotator cuff repair provide large clinical benefits, with few adverse events. There is strong evidence of equivalent clinical improvements. TRIAL REGISTRATION: NCT00128076.

p16INK4a Regulates Cellular Senescence in PD-1-Expressing Human T Cells.

T-cell dysfunction arising upon repeated antigen exposure prevents effective immunity and immunotherapy. Using various clinically and physiologically relevant systems, we show that a prominent feature of PD-1-expressing exhausted T cells is the development of cellular senescence features both in vivo and ex vivo. This is associated with p16INK4a expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells. We show that these T cells accumulate DNA damage and activate the p38MAPK signaling pathway, which preferentially leads to p16INK4a upregulation. However, in highly dysfunctional T cells, p38MAPK inhibition does not restore functionality despite attenuating senescence features. In contrast, p16INK4a targeting can improve T-cell functionality in exhausted CAR T cells. Collectively, this work provides insights into the development of T-cell dysfunction and identifies T-cell senescence as a potential target in immunotherapy.

CD5 levels define functionally heterogeneous populations of naïve human CD4+ T cells.

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naïve T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear. Our study demonstrates that CD5 levels correlate with TCR signal strength in human naïve CD4+ T cells. Further, we describe a relationship between CD5 levels on naïve human CD4+ T cells and binding affinity to foreign peptide, in addition to a predominance of CD5hi T cells in the memory compartment. Differences in gene expression and biases in cytokine production potential between CD5lo and CD5hi naïve human CD4+ T cells are consistent with observations in mice. Together, these data validate the use of CD5 surface levels as a marker of heterogeneity among human naïve CD4+ T cells with important implications for the identification of functionally biased T- cell populations that can be exploited to improve the efficacy of adoptive cell therapies.

Differential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates.

Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here, we establish bacterial artificial chromosome (BAC)-transgenic mouse lines with biased mTEClo or mTEChi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEClo supports TCRαß+ CD8αα intraepithelial lymphocyte development; meanwhile, mTEChi-restricted expression preferentially induces Treg differentiation of antigen-specific cells in these models to impact control of infectious agents and tumor growth. In summary, our data suggest that mTEC subsets may have a function in directing distinct mechanisms of T cell tolerance.

A randomised trial of observational learning from 2D and 3D models in robotically assisted surgery.

BACKGROUND: Advances in 3D technology mean that both robotic surgical devices and surgical simulators can now incorporate stereoscopic viewing capabilities. While depth information may benefit robotic surgical performance, it is unclear whether 3D viewing also aids skill acquisition when learning from observing others. As observational learning plays a major role in surgical skills training, this study aimed to evaluate whether 3D viewing provides learning benefits in a robotically assisted surgical task. METHODS: 90 medical students were assigned to either (1) 2D or (2) 3D observation of a consultant surgeon performing a training task on the daVinci S robotic system, or (3) a no observation control, in a randomised parallel design. Subsequent performance and instrument movement metrics were assessed immediately following observation and at one-week retention. RESULTS: Both 2D and 3D groups outperformed no observation controls following the observation intervention (ps < 0.05), but there was no difference between 2D and 3D groups at any of the timepoints. There was also no difference in movement parameters between groups. CONCLUSIONS: While 3D viewing systems may have beneficial effects for surgical performance, these results suggest that depth information has limited utility during observational learning of surgical skills in novices. The task constraints and end goals may provide more important information for learning than the relative motion of surgical instruments in 3D space.

Development of a vibration haptic simulator for shoulder arthroplasty.

PURPOSE: Glenoid reaming is a technically challenging step during shoulder arthroplasty that could possibly be learned during simulation training. Creation of a realistic simulation using vibration feedback in this context is innovative. Our study focused on the development and internal validation of a novel glenoid reaming simulator for potential use as a training tool. METHODS: Vibration and force profiles associated with glenoid reaming were quantified during a cadaveric experiment. Subsequently, a simulator was fabricated utilizing a haptic vibration transducer with high- and low-fidelity amplifiers; system calibration was performed matching vibration peak-peak values for both amplifiers. Eight experts performed simulated reaming trials. The experts were asked to identify isolated layer profiles produced by the simulator. Additionally, experts' efficiency to successfully perform a simulated glenoid ream based solely on vibration feedback was recorded. RESULTS: Cadaveric experimental cartilage reaming produced lower vibrations compared to subchondral and cancellous bones ([Formula: see text]). Gain calibration of a lower-fidelity (3.5 [Formula: see text] and higher-fidelity (3.4 [Formula: see text] amplifier resulted in values similar to the cadaveric experimental benchmark (3.5 [Formula: see text]. When identifying random tissue layer samples, experts were correct [Formula: see text] of the time and success rate varied with tissue type ([Formula: see text]). During simulated reaming, the experts stopped at the targeted subchondral bone with a success rate of [Formula: see text]. The fidelity of the simulation did not have an effect on accuracy, applied force, or reaming time ([Formula: see text]). However, the applied force tended to increase with trial number ([Formula: see text]). CONCLUSIONS: Development of the glenoid reaming simulator, coupled with expert evaluation furthered our understanding of the role of haptic vibration feedback during glenoid reaming. This study was the first to (1) propose, develop and examine simulated glenoid reaming, and (2) explore the use of haptic vibration feedback in the realm of shoulder arthroplasty.

Development of a physical shoulder simulator for the training of basic arthroscopic skills.

BACKGROUND: Orthopaedic training programs are incorporating arthroscopic simulations into their residency curricula. There is a need for a physical shoulder simulator that accommodates lateral decubitus and beach chair positions, has realistic anatomy, allows for an objective measure of performance and provides feedback to trainees. METHODS: A physical shoulder simulator was developed for training basic arthroscopic skills. Sensors were embedded in the simulator to provide a means to assess performance. Subjects of varying skill level were invited to use the simulator and their performance was objectively assessed. RESULTS: Novice subjects improved their performance after practice with the simulator. A survey completed by experts recognized the simulator as a valuable tool for training basic arthroscopic skills. CONCLUSIONS: The physical shoulder simulator helps train novices in basic arthroscopic skills and provides objective measures of performance. By using the physical shoulder simulator, residents could improve their basic arthroscopic skills, resulting in improved patient safety.

Observational Learning During Simulation-Based Training in Arthroscopy: Is It Useful to Novices?

OBJECTIVE: Observing experts constitutes an important and common learning experience for surgical residents before operating under direct guidance. However, studies suggest that exclusively observing experts may induce suboptimal motor learning, and watching errors from non-experts performing simple motor tasks may generate better performance. We investigated whether observational learning is transferrable to arthroscopy learning using virtual reality (VR) simulation. SETTING/DESIGN: In our surgical simulation laboratory, we compared students learning basic skills on a VR arthroscopy simulator after watching an expert video demonstration of VR arthroscopy tasks or a non-expert video demonstration of the same tasks to a Control group without video demonstration. Ninety students in 3 observing groups (expert, non-expert, and Control) subsequently completed the same procedure on a VR arthroscopy simulator. We hypothesized the non-expert-watching group would outperform the expert-watching group, and both groups to outperform the Control group. We examined performance pretest, posttest, and 1 week later. PARTICIPANTS: Participants were recruited from the final year of medical school and the very early first year of surgical residency training programs (orthopaedic surgery, urology, plastic surgery, and general surgery) at Western University (Ontario, Canada). RESULTS: All participants improved their overall performance from pretest to retention (p < 0.001). At initial retention testing, non-expert-watching group outperformed the other groups in camera path length p < 0.05 and time to completion, p < 0.05, and both the expert/non-expert groups surpassed the Control group in camera path length (p < 0.05). CONCLUSION: We suggest that error-observation may contribute to skills improvement in the non-expert-watching group. Allowing novices to observe techniques/errors of other novices may assist internalization of specific movements/skills required for effective motor performances. This study highlights the potential effect of observational learning on surgical skills acquisition and offers preliminary evidence for peer-based practice (combined non-experts and experts) as a complementary surgical motor skills training strategy.

Analysis of Energy-Based Metrics for Laparoscopic Skills Assessment.

OBJECTIVE: The complexity of minimally invasive surgery (MIS) requires that trainees practice MIS skills in numerous training sessions. The goal of these training sessions is to learn how to move the instruments smoothly without damaging the surrounding tissue and achieving operative tasks with accuracy. In order to enhance the efficiency of these training sessions, the proficiency of the trainees should be assessed using an objective assessment method. Several performance metrics have been proposed and analyzed for MIS tasks. The differentiation of various levels of expertise is limited without the presence of an external evaluator. METHODS: In this study, novel objective performance metrics are proposed based on mechanical energy expenditure and work. The three components of these metrics are potential energy, kinetic energy, and work. These components are optimally combined through both one-step and two-step methods. Evaluation of these metrics is accomplished for suturing and knot-tying tasks based on the performance of 30 subjects across four levels of experience. RESULTS: The results of this study show that the one-step combined metric provides 47 and 60 accuracy in determining the level of expertise of subjects for the suturing and knot-tying tasks, respectively. The two-step combined metric provided 67 accuracy for both of the tasks studied. CONCLUSION: The results indicate that energy expenditure is a useful metric for developing objective and efficient assessment methods. SIGNIFICANCE: These metrics can be used to evaluate and determine the proficiency levels of trainees, provide feedback and, consequently, enhance surgical simulators.

The effect of observing novice and expert performance on acquisition of surgical skills on a robotic platform.

BACKGROUND: Observational learning plays an important role in surgical skills training, following the traditional model of learning from expertise. Recent findings have, however, highlighted the benefit of observing not only expert performance but also error-strewn performance. The aim of this study was to determine which model (novice vs. expert) would lead to the greatest benefits when learning robotically assisted surgical skills. METHODS: 120 medical students with no prior experience of robotically-assisted surgery completed a ring-carrying training task on three occasions; baseline, post-intervention and at one-week follow-up. The observation intervention consisted of a video model performing the ring-carrying task, with participants randomly assigned to view an expert model, a novice model, a mixed expert/novice model or no observation (control group). Participants were assessed for task performance and surgical instrument control. RESULTS: There were significant group differences post-intervention, with expert and novice observation groups outperforming the control group, but there were no clear group differences at a retention test one week later. There was no difference in performance between the expert-observing and error-observing groups. CONCLUSIONS: Similar benefits were found when observing the traditional expert model or the error-strewn model, suggesting that viewing poor performance may be as beneficial as viewing expertise in the early acquisition of robotic surgical skills. Further work is required to understand, then inform, the optimal curriculum design when utilising observational learning in surgical training.

Clinical Assessment of Physical Examination Maneuvers for Superior Labral Anterior to Posterior Lesions.

Purpose Shoulder pain and disability pose a diagnostic challenge owing to the numerous etiologies and the potential for multiple disorders to exist simultaneously. The evidence to support the use of clinical tests for superior labral anterior to posterior complex (SLAP) is weak or absent. The purpose of this study is to determine the diagnostic validity of physical examination maneuvers for SLAP lesions by performing a methodologically rigorous, clinically applicable study. Methods We recruited consecutive new shoulder patients reporting pain and/or disability. The physician took a history and indicated their certainty about each possible diagnosis ("certain the diagnosis is absent/present," or "uncertain requires further testing"). The clinician performed the physical tests for diagnoses where uncertainty remained. Magnetic resonance imaging arthrogram and arthroscopic examination were the gold standards. We calculated sensitivity, specificity, and likelihood ratios (LRs) and investigated whether combinations of the top tests provided stronger predictions. Results Ninety-three patients underwent physical examination for SLAP lesions. When using the presence of a SLAP lesion (Types I-V) as disease positive, none of the tests was sensitive (10.3-33.3) although they were moderately specific (61.3-92.6). When disease positive was defined as repaired SLAP lesion (including biceps tenodesis or tenotomy), the sensitivity (10.5-38.7) and specificity (70.6-93.8) of tests improved although not by a substantial amount. None of the tests was found to be clinically useful for predicting repairable SLAP lesions with all LRs close to one. The compression rotation test had the best LR for both definitions of disease (SLAP tear present = 1.8 and SLAP repaired = 1.67). There was no optimal combination of tests for diagnosing repairable SLAP lesions, with at least two tests positive providing the best combination of measurement properties (sensitivity 46.1% and specificity 64.7%). Conclusion Our study demonstrates that the physical examination tests for SLAP lesions are poor diagnostic indicators of disease. Performing a combination of tests will likely help, although the magnitude of the improvement is minimal. These authors caution clinicians placing confidence in the physical examination tests for SLAP lesions rather we suggest that clinicians rely on diagnostic imaging to confirm this diagnosis.

Diagnostic Validity of Patient-Reported History for Shoulder Pathology.

Objective The purpose of this article is to determine whether patient-reported history items are predictive of shoulder pathology and have the potential for use in triaging patients with shoulder pathology to orthopaedic outpatient clinics. Setting It is set at two tertiary orthopaedic clinics. Patients All new patients reporting pain and/or disability of the shoulder joint were prospectively recruited. A total of 193 patients were enrolled, 15 of whom withdrew, leaving 178 patients composing the study sample. Design Patients completed a questionnaire on the history of their pathology, then the surgeon took a thorough history indicating the most likely diagnosis. The clinician then performed appropriate physical examination. Arthroscopy was the reference standard for those undergoing surgery and magnetic resonance imaging (MRI) with arthrogram for all others. We calculated the sensitivity, specificity, and likelihood ratios (LRs) of history items alone and in combination. We used the LRs to generate a clinical decision algorithm. Main Outcome Measures Diagnosis was determined through arthroscopy or MRI arthrogram. Reporting was standardized to ensure review of all structures. Results The physical examination and history agreed in 75% of cases. Of those that did not agree, the physical examination misdirected the diagnosis in 47% of our cases. In particular, history items were strong predictors of anterior and posterior instability and subscapularis tears and were combined in a tool to be utilized for screening patients. Conclusion The patient-reported history items were effective for diagnosing shoulder pathology and should be considered for use in a triaging instrument.

Efficacy of a Virus-Like Nanoparticle As Treatment for a Chronic Viral Infection Is Hindered by IRAK1 Regulation and Antibody Interference.

Although vaccination has been an effective way of preventing infections ever since the eighteenth century, the generation of therapeutic vaccines and immunotherapies is still a work in progress. A number of challenges impede the development of these therapeutic approaches such as safety issues related to the administration of whole pathogens whether attenuated or inactivated. One safe alternative to classical vaccination methods gaining recognition is the use of nanoparticles, whether synthetic or naturally derived. We have recently demonstrated that the papaya mosaic virus (PapMV)-like nanoparticle can be used as a prophylactic vaccine against various viral and bacterial infections through the induction of protective humoral and cellular immune responses. Moreover, PapMV is also very efficient when used as an immune adjuvant in an immunotherapeutic setting at slowing down the growth of aggressive mouse melanoma tumors in a type I interferon (IFN-I)-dependent manner. In the present study, we were interested in exploiting the capacity of PapMV of inducing robust IFN-I production as treatment for the chronic viral infection model lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl13). Treatment of LCMV Cl13-infected mice with two systemic administrations of PapMV was ineffective, as shown by the lack of changes in viral titers and immune response to LCMV following treatment. Moreover, IFN-α production following PapMV administration was almost completely abolished in LCMV-infected mice. To better isolate the mechanisms at play, we determined the influence of a pretreatment with PapMV on secondary PapMV administration, therefore eliminating potential variables emanating from the infection. Pretreatment with PapMV led to the same outcome as an LCMV infection in that IFN-α production following secondary PapMV immunization was abrogated for up to 50 days while immune activation was also dramatically impaired. We showed that two distinct and overlapping mechanisms were responsible for this outcome. While short-term inhibition was partially the result of interleukin-1 receptor-associated kinase 1 degradation, a crucial component of the toll-like receptor 7 signaling pathway, long-term inhibition was mainly due to interference by PapMV-specific antibodies. Thus, we identified a possible pitfall in the use of virus-like particles for the systemic treatment of chronic viral infections and discuss mitigating alternatives to circumvent these potential problems.

Potentiating Cancer Immunotherapy Using Papaya Mosaic Virus-Derived Nanoparticles.

The recent development of novel immunotherapies is revolutionizing cancer treatment. These include, for example, immune checkpoint blockade, immunomodulation, or therapeutic vaccination. Although effective on their own, combining multiple approaches will most likely be required in order to achieve the maximal therapeutic benefit. In this regard, the papaya mosaic virus nanoparticle (PapMV) has shown tremendous potential as (i) an immunostimulatory molecule, (ii) an adjuvant, and (iii) a vaccine platform through its intrinsic capacity to activate the innate immune response in an IFN-α-dependent manner. Here, we demonstrate that intratumor administration of PapMV significantly slows down melanoma progression and prolongs survival. This correlates with enhanced chemokine and pro-inflammatory-cytokine production in the tumor and increased immune-cell infiltration. Proportions of total and tumor-specific CD8(+) T cells dramatically increase following PapMV treatment whereas those of myeloid-derived suppressor cells (MDSC) concomitantly decrease. Moreover, systemic PapMV administration prevents metastatic tumor-implantation in the lungs. Importantly, PapMV also synergistically improves the therapeutic benefit of dendritic cell (DC)-based vaccination and PD-1 blockade by potentiating antitumor immune responses. This study illustrates the immunostimulatory potential of a plant virus-derived nanoparticle for cancer therapy either alone or in conjunction with other promising immunotherapies in clinical development.

Energy-based metrics for laparoscopic skills assessment.

The growing popularity of minimally invasive surgery (MIS) can be attributed to its advantages, which include reduced post-operative pain, a shorter hospital stay, and faster recovery. However, MIS requires extensive training for surgeons to become experts in their field of practice. Different assessment methods have been proposed for evaluating the performance of surgeons and residents on surgical simulators. Nonetheless, optimal objective performance measures are still lacking. In this study, three metrics for minimally invasive skills assessment are proposed based on energy expenditure: work, potential energy and kinetic energy. In order to evaluate these metrics, two laparoscopic tasks consisting of suturing and knot-tying are investigated, involving expert and novice subjects. This study shows that measures based on energy expenditure can be used for skills assessment: all three metrics can discriminate between experts and novices for the two tasks investigated here. These measures can also reflect the efficiency of subjects when performing MIS tasks. Further modification and investigation of these metrics can extend their use to different tasks and for discriminating between various levels of experience.