PKA Activity-Driven Modulation of Bidirectional Long-Distance transport of Lysosomal vesicles During Synapse Maintenance.

The bidirectional long-distance transport of organelles is crucial for cell body-synapse communication. However, the mechanisms by which this transport is modulated for synapse formation, maintenance, and plasticity are not fully understood. Here, we demonstrate through quantitative analyses that maintaining sensory neuron-motor neuron synapses in the Aplysia gill-siphon withdrawal reflex is linked to a sustained reduction in the retrograde transport of lysosomal vesicles in sensory neurons. Interestingly, while mitochondrial transport in the anterograde direction increases within 12 hours of synapse formation, the reduction in lysosomal vesicle retrograde transport appears three days after synapse formation. Moreover, we find that formation of new synapses during learning induced by neuromodulatory neurotransmitter serotonin further reduces lysosomal vesicle transport within 24 hours, whereas mitochondrial transport increases in the anterograde direction within one hour of exposure. Pharmacological inhibition of several signaling pathways pinpoints PKA as a key regulator of retrograde transport of lysosomal vesicles during synapse maintenance. These results demonstrate that synapse formation leads to organelle-specific and direction specific enduring changes in long-distance transport, offering insights into the mechanisms underlying synapse maintenance and plasticity.

A simple active fluid model unites cytokinesis, cell crawling, and axonal outgrowth.

Axonal outgrowth, cell crawling, and cytokinesis utilize actomyosin, microtubule-based motors, cytoskeletal dynamics, and substrate adhesions to produce traction forces and bulk cellular motion. While it has long been appreciated that growth cones resemble crawling cells and that the mechanisms that drive cytokinesis help power cell crawling, they are typically viewed as unique processes. To better understand the relationship between these modes of motility, here, we developed a unified active fluid model of cytokinesis, amoeboid migration, mesenchymal migration, neuronal migration, and axonal outgrowth in terms of cytoskeletal flow, adhesions, viscosity, and force generation. Using numerical modeling, we fit subcellular velocity profiles of the motions of cytoskeletal structures and docked organelles from previously published studies to infer underlying patterns of force generation and adhesion. Our results indicate that, during cytokinesis, there is a primary converge zone at the cleavage furrow that drives flow towards it; adhesions are symmetric across the cell, and as a result, cells are stationary. In mesenchymal, amoeboid, and neuronal migration, the site of the converge zone shifts, and differences in adhesion between the front and back of the cell drive crawling. During neuronal migration and axonal outgrowth, the primary convergence zone lies within the growth cone, which drives actin retrograde flow in the P-domain and bulk anterograde flow of the axonal shaft. They differ in that during neuronal migration, the cell body is weakly attached to the substrate and thus moves forward at the same velocity as the axon. In contrast, during axonal outgrowth, the cell body strongly adheres to the substrate and remains stationary, resulting in a decrease in flow velocity away from the growth cone. The simplicity with which cytokinesis, cell crawling, and axonal outgrowth can be modeled by varying coefficients in a simple model suggests a deep connection between them.

The Risk of Sympathetic Ophthalmia Associated with Open-Globe Injury Management Strategies: A Meta-analysis.

TOPIC: Sympathetic ophthalmia (SO) is a sight-threatening granulomatous panuveitis caused by a sensitizing event. Primary enucleation or primary evisceration, versus primary repair, as a risk management strategy after open-globe injury (OGI) remains controversial. CLINICAL RELEVANCE: This systematic review was conducted to report the incidence of SO after primary repair compared with that of after primary enucleation or primary evisceration. This enabled the reporting of an estimated number needed to treat. METHODS: Five journal databases were searched. This review was registered with International Prospective Register of Systematic Reviews (identifier, CRD42021262616). Searches were carried out on June 29, 2021, and were updated on December 10, 2022. Prospective or retrospective studies that reported outcomes (including SO or lack of SO) in a patient population who underwent either primary repair and primary enucleation or primary evisceration were included. A systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Random effects modelling was used to estimate pooled SO rates and absolute risk reduction (ARR). RESULTS: Eight studies reporting SO as an outcome were included in total. The included studies contained 7500 patients and 7635 OGIs. In total, 7620 OGIs met the criteria for inclusion in this analysis; SO developed in 21 patients with OGI. When all included studies were pooled, the estimated SO rate was 0.12% (95% confidence interval [CI], 0.00%-0.25%) after OGI. Of 779 patients who underwent primary enucleation or primary evisceration, no SO cases were reported, resulting in a pooled SO estimate of 0.05% (95% CI, 0.00%-0.21%). For primary repair, the pooled estimate of SO rate was 0.15% (95% CI, 0.00%-0.33%). The ARR using a random effects model was -0.0010 (in favour of eye removal; 95% CI, -0.0031 [in favor of eye removal] to 0.0011 [in favor of primary repair]). Grading of Recommendations, Assessment, Development, and Evaluations analysis highlighted a low certainty of evidence because the included studies were observational, and a risk of bias resulted from missing data. DISCUSSION: Based on the available data, no evidence exists that primary enucleation or primary evisceration reduce the risk of secondary SO. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Use of Preoperative Prophylactic Systemic Antibiotics for the Prevention of Endopthalmitis in Open Globe Injuries: A Meta-Analysis.

TOPIC: This study reports the effect of systemic prophylactic antibiotics (and their route) on the risk of endophthalmitis after open globe injury (OGI). CLINICAL RELEVANCE: Endophthalmitis is a major complication of OGI; it can lead to rapid sight loss in the affected eye. The administration of systemic antibiotic prophylaxis is common practice in some health care systems, although there is no consensus on their use. METHODS: PubMed, CENTRAL, Web of Science, CINAHL, and Embase were searched. This was completed July 6, 2021 and updated December 10, 2022. We included randomized and nonrandomized prospective studies which reported the rate of post-OGI endophthalmitis when systemic preoperative antibiotic prophylaxis (via the oral or IV route) was given. The Cochrane Risk of Bias tool and ROBINS-I tool were used for assessing the risk of bias. Where meta-analysis was performed, results were reported as an odds ratio. PROSPERO registration: CRD42021271271. RESULTS: Three studies were included. One prospective observational study compared outcomes of patients who had received systemic or no systemic preoperative antibiotics. The endophthalmitis rates reported were 3.75% and 4.91% in the systemic and no systemic preoperative antibiotics groups, a nonsignificant difference (P = 0.68). Two randomized controlled trials were included (1555 patients). The rates of endophthalmitis were 17 events in 751 patients (2.26%) and 17 events in 804 patients (2.11%) in the oral antibiotics and IV (± oral) antibiotics groups, respectively. Meta-analysis demonstrated no significant differences between groups (odds ratio, 1.07; 95% confidence interval, 0.54-2.12). CONCLUSIONS: The incidences of endophthalmitis after OGI were low with and without systemic antibiotic prophylaxis, although high-risk cases were excluded in the included studies. When antibiotic prophylaxis is considered, there is moderate evidence that oral antibiotic administration is noninferior to IV. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Applying a Military Teleophthalmology Mobile App in a Noncombat Emergent Care Setting.

INTRODUCTION: Teleophthalmology has a natural role in the military due to the inherent organization of its medical system, which provides care to patients in remote locations around the world. Improving access to ophthalmic care enhances force readiness because ocular trauma and disease can cause vision impairment or blindness and can occur anywhere service members are located. Recently, a secure, Health Insurance Portability and Accountability Act-compliant mobile phone application (app) for teleophthalmology called Forward Operating Base Expert Telemedicine Resource Utilizing Mobile Application for Trauma (FOXTROT) was beta tested in Afghanistan and demonstrated that this solution can improve and extend ophthalmic care in a deployed environment. There are few civilian or military teleophthalmology solutions for ocular trauma and disease in an urgent or emergent ophthalmic care setting. Civilian teleophthalmology solutions have largely been developed for disease-specific models of care. In this work, we address this gap by testing the FOXTROT app in a non-deployed, emergent care setting. MATERIALS AND METHODS: We evaluated the use of the teleophthalmology mobile phone app (FOXTROT) in a non-deployed military setting at the Malcolm Grow Medical Clinics and Surgery Center at Joint Base Andrews in Maryland. Consults from the emergent care center were placed by providers using the app, and the on-call ophthalmologist responded with treatment and management recommendations. The primary outcomes were response within the requested time, visual acuity tested in both eyes, agreement between the teleophthalmology and the final diagnosis, and the number of communication or technical errors that prevented the completion of consults. The secondary outcomes were average response time and the number of consults uploaded to the medical record. RESULTS: From October 2020 to January 2022, 109 consults were received. Ten consults had communication or technical errors that prevented the completion of consults within the app and were excluded from the analysis of completed consults. Of the 99 completed consults, responses were given within the requested time in 95 (96.0%), with the average response time in 11 minutes 48 seconds (95% confidence interval, 8 minutes 57 seconds to 14 minutes 41 seconds). Visual acuity was tested in both eyes in 56 (56.6%). There was agreement between the teleophthalmology diagnosis and the final diagnosisin 40 of 50 (80.0%) consults with both a teleophthalmology and final diagnosis. Ninety-eight (99.0%) consults were uploaded to the patient's medical record. CONCLUSIONS: Beta testing of a teleophthalmology mobile phone app (FOXTROT) in a noncombat emergent care setting demonstrated that this solution can extend ophthalmic care in this environment at a military treatment facility. However, improvements in the reliability of the platform are needed in future developments to reduce communication and technical errors.

Live Imaging and Quantitative Analysis of Organelle Transport in Sensory Neurons of Aplysia Californica.

Axonal transport moves proteins, RNAs, and organelles between the soma and synapses to support synaptic function and activity-dependent changes in synaptic strength. This transport is impaired in several neurodegenerative disorders such as Alzheimer's disease. Thus, it is critical to understand the regulation and underlying mechanisms of the transport process. Aplysia californica provides a powerful experimental system for studying the interplay between synaptic activity and transport because its defined synaptic circuits can be built in-vitro. Advantages include precise pre- and postsynaptic manipulation, and high-resolution imaging of axonal transport. Here, we describe methodologies for the quantitative analysis of axonal transport in Aplysia sensory neurons.

Needle decompression of the eye! Emergent management of a vision threatening surgical complication.

Acute angle-closure glaucoma (AACG) is a medical emergency that can cause permanent visual deficits without prompt recognition. From 2006 to 2011, nearly 12 million visits to emergency departments (ED) in the United States were ophthalmologic in nature, making it crucial for emergency physicians to be familiar with the diagnosis and treatment of ophthalmologic emergencies. AACG can be precipitated by several mechanisms including pupillary block, anticholinergic medications, and sympathomimetic medications. We present a rare case of angle-closure glaucoma status post pneumatic retinopexy with cryotherapy due to migration of an intravitreal gas bubble into the anterior chamber with emphasis on understanding how retinal surgery types lead to significant differences in management.

Effectiveness of the Ophthalmological Training Component of the STOMP (Simulation Training for Operational Medical Providers) Curriculum.

INTRODUCTION: Simulation has been used in medicine to train clinicians to manage a variety of clinical scenarios. A key adaptation of the use of simulation in military healthcare occurred in 2015 with the development of the STOMP (Simulation Training for Operational Medical Providers) curriculum, a specific curriculum designed for the intern (PGY-1) trained physicians being sent into the military to practice primary care. Despite showing the curriculum's influence on self-perceived comfort scores, no study has determined whether simulation is an effective means of improving general medical officer (GMO) physicians' skills compared to other traditional styles of education. Specifically, this study sought to determine whether simulation-based education (SBE) of ophthalmologic skills improves GMO physicians' clinical performance, as compared to traditional didactic-based instruction. METHODS: The study, conducted at Naval Medical Center Portsmouth, included GMO physicians who were enrolled in the 2019 STOMP class. Following a brief overview of the study, GMO physicians who elected to participate in the study were randomized to either SBE or lecture-based training for three commonly used ophthalmological procedures: slit lamp exam, tonometry, and corneal foreign body removal. After completing the simulation and lecture-based education training sessions, participants' procedural performance was evaluated utilizing a locally developed performance checklist, and completion time for each of the three procedures was recorded. Data were analyzed using the t-test and Mann-Whitney test. A significance level of 0.05 was considered to be statistically significant. RESULTS: Of the 50 consented participants, 46 completed the study. The mean overall completion scores for the performance checklists were significantly higher for the SBE group (n=26) compared to the lecture group (n=20) [80% (95% CI 78-82%) vs 41% (95% CI 35-47%), respectively]. Time to completion of the individual tasks was also significantly shorter for the SBE group compared to the lecture group (with mean differences ranging from 27 to 126 seconds, all p<.05). CONCLUSIONS: Simulation-based training appeared to be more effective at teaching three ophthalmological procedures (slit lamp exam, tonometry, and corneal foreign body removal) to GMO physicians compared to didactic-based instruction alone.

Military Teleophthalmology in Afghanistan Using Mobile Phone Application.

IMPORTANCE: The coronavirus disease 2019 pandemic has highlighted the need to expand telemedicine solutions. OBJECTIVE: To beta test a secure teleophthalmology mobile app at military treatment facilities in Afghanistan. DESIGN, SETTING, AND PARTICIPANTS: This prospective case series included 16 military treatment facilities at diverse roles of care including forward operating bases in Afghanistan and 1 location outside of Afghanistan. Thirty point-of-care medics and medical professionals were included from September to November 2019. INTERVENTIONS: Users placed teleophthalmology consults on their mobile phone using the mobile eye care app, and an expeditionary ophthalmologist stationed at a military hospital in Afghanistan responded. Users graded the mobile app using a rating scale from 1 to 5, with 1 being very dissatisfied and 5 being very satisfied. MAIN OUTCOMES AND MEASURES: Mean initial response time, agreement between the teleophthalmology diagnosis and final diagnosis, treatment and management following recommendations outlined in the Joint Trauma System clinical practice guidelines, prevention of the need for aeromedical evacuation, user satisfaction, and security and the Health Insurance Portability and Accountability Act compliance of consult. RESULTS: There were 28 consults placed over 6 weeks by 18 different users that were received by the expeditionary ophthalmologist. The mean (SD) patient age was 30.3 (9.8) years. Most patients were male (26 [93%]) and active duty US military (22 [78%]). The mean initial response time was 3 minutes 58 seconds (95% CI, 2 minutes 30 seconds to 5 minutes 26 seconds). There was agreement between the teleophthalmology diagnosis and final diagnosis in 24 consults (86%; 95% CI, 72%-100%). The treatment and management followed recommendations outlined in the Joint Trauma System Clinical Practice Guidelines for Eye Trauma: Initial Care in 28 consults (100%). Teleophthalmology consultation prevented the need for aeromedical evacuation in 4 consults (14%; 95% CI, 0.7%-28%). The patient returned to duty in 15 consults (54%; 95% CI, 34%-73%). Median overall satisfaction was 5 (minimum, 3; maximum, 5). All 28 consults (100%) were secure and compliant with the Health Insurance Portability and Accountability Act. CONCLUSIONS AND RELEVANCE: While only a limited number of consults were evaluated, this study suggests that teleophthalmology mobile phone apps may improve and extend ophthalmic care in combat zones.

Dynein-mediated microtubule translocation powering neurite outgrowth in chick and Aplysia neurons requires microtubule assembly.

Previously, we have shown that bulk microtubule (MT) movement correlates with neurite elongation, and blocking either dynein activity or MT assembly inhibits both processes. However, whether the contributions of MT dynamics and dynein activity to neurite elongation are separate or interdependent is unclear. Here, we investigated the underlying mechanism by testing the roles of dynein and MT assembly in neurite elongation of Aplysia and chick neurites using time-lapse imaging, fluorescent speckle microscopy, super-resolution imaging and biophysical analysis. Pharmacologically inhibiting either dynein activity or MT assembly reduced neurite elongation rates as well as bulk and individual MT anterograde translocation. Simultaneously suppressing both processes did not have additive effects, suggesting a shared mechanism of action. Single-molecule switching nanoscopy revealed that inhibition of MT assembly decreased the association of dynein with MTs. Finally, inhibiting MT assembly prevented the rise in tension induced by dynein inhibition. Taken together, our results suggest that MT assembly is required for dynein-driven MT translocation and neurite outgrowth.

Diplopia and Strabismus After Corneal Refractive Surgery.

INTRODUCTION: Diplopia and strabismus are known complications after corneal refractive surgery (CRS). Within the U.S. Armed Forces, refractive surgery is used to improve the operational readiness of the service member, and these complications could cause significant degradation to their capability. This study was performed in order to identify the incidence of strabismus and diplopia following CRS within the U.S. Military Health System. METHODS: A retrospective review of all patients who underwent photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK) in the Department of Defense from January 2006 through September 2013 was designed and approved by the Naval Medical Center Portsmouth Institutional Review Board. The military health system data mart was queried for all patients who underwent one of these procedures and subsequently had an International Classification of Disease-9 code for any strabismus or diplopia through 2014 allowing at least 1 year of follow-up. We then calculated the incidence of both diplopia and strabismus for these procedures as the primary measure and the overall prevalence as a secondary measure. RESULTS: A total of 108,157 patients underwent PRK or LASIK during our study period with 41 of these patients subsequently having a diagnosis of diplopia or strabismus. After chart review, 16 of these patients were excluded resulting in 25 patients for inclusion in either the strabismus (23 patients, 0.02%) or diplopia (3 patients, 0.003%) cohorts with one patient having both. Of the 23 patients with postoperative strabismus, 4 were new cases giving an incidence of 0.004% and 2 new cases of diplopia for an incidence of 0.002%. CONCLUSION: Diplopia and strabismus are rare complications after CRS in the U.S. military population. These procedures continue to increase the operational readiness of our service members with minimal risk of these potentially debilitating complications. Overall, this study provides support for the continued use of PRK and LASIK despite study limitations related to the use of large databases for retrospective review. Future prospective studies using delineated preoperative and postoperative examinations with sensorimotor testing included may be able to resolve the limitations of this study.

Synapse Formation Activates a Transcriptional Program for Persistent Enhancement in the Bi-directional Transport of Mitochondria.

Mechanisms that regulate the bi-directional transport of mitochondria in neurons for maintaining functional synaptic connections are poorly understood. Here, we show that in the pre-synaptic sensory neurons of the Aplysia gill withdrawal reflex, the formation of functional synapses leads to persistent enhancement in the flux of bi-directional mitochondrial transport. In the absence of a functional synapse, activation of cAMP signaling is sufficient to enhance bi-directional transport in sensory neurons. Furthermore, persistent enhancement in transport does not depend on NMDA and AMPA receptor signaling nor signaling from the post-synaptic neuronal cell body, but it is dependent on transcription and protein synthesis in the pre-synaptic neuron. We identified ∼4,000 differentially enriched transcripts in pre-synaptic neurons, suggesting a long-term change in the transcriptional program produced by synapse formation. These results provide insights into the regulation of bi-directional mitochondrial transport for synapse maintenance.

An Integrated Cytoskeletal Model of Neurite Outgrowth.

Neurite outgrowth underlies the wiring of the nervous system during development and regeneration. Despite a significant body of research, the underlying cytoskeletal mechanics of growth and guidance are not fully understood, and the relative contributions of individual cytoskeletal processes to neurite growth are controversial. Here, we review the structural organization and biophysical properties of neurons to make a semi-quantitative comparison of the relative contributions of different processes to neurite growth. From this, we develop the idea that neurons are active fluids, which generate strong contractile forces in the growth cone and weaker contractile forces along the axon. As a result of subcellular gradients in forces and material properties, actin flows rapidly rearward in the growth cone periphery, and microtubules flow forward in bulk along the axon. With this framework, an integrated model of neurite outgrowth is proposed that hopefully will guide new approaches to stimulate neuronal growth.

Acute Onset Esotropia From Excessive Smartphone Use in a Teenager.

Acute acquired comitant esotropia secondary to smart-phone use is a newly described phenomenon. This case report describes a boy with acute acquired comitant esotropia due to prolonged smartphone use who had improvement in binocular function after cessation of near work for several weeks. [J Pediatr Ophthalmol Strabismus. 2018;55:e42-e44.].

Modeling the Axon as an Active Partner with the Growth Cone in Axonal Elongation.

Forces generated by the growth cone are vital for the proper development of the axon and thus brain function. Although recent experiments show that forces are generated along the axon, it is unknown whether the axon plays a direct role in controlling growth cone advance. Here, we use analytic and finite element modeling of microtubule dynamics and the activity of the molecular motors myosin and dynein to investigate mechanical force balance along the length of the axon and its effects on axonal outgrowth. Our modeling indicates that the paradoxical effects of stabilizing microtubules and the consequences of microtubule disassembly on axonal outgrowth can be explained by changes in the passive and active mechanical properties of axons. Our findings suggest that a full understanding of growth cone motility requires a consideration of the mechanical contributions of the axon. Our study not only has potential applications during neurodevelopment but might also help identify strategies to manipulate and promote axonal regrowth to treat neurodegeneration.

Neurite elongation is highly correlated with bulk forward translocation of microtubules.

During the development of the nervous system and regeneration following injury, microtubules (MTs) are required for neurite elongation. Whether this elongation occurs primarily through tubulin assembly at the tip of the axon, the transport of individual MTs, or because MTs translocate forward in bulk is unclear. Using fluorescent speckle microscopy (FSM), differential interference contrast (DIC), and phase contrast microscopy, we tracked the movement of MTs, phase dense material, and docked mitochondria in chick sensory and Aplysia bag cell neurons growing rapidly on physiological substrates. In all cases, we find that MTs and other neuritic components move forward in bulk at a rate that on average matches the velocity of neurite elongation. To better understand whether and why MT assembly is required for bulk translocation, we disrupted it with nocodazole. We found this blocked the forward bulk advance of material along the neurite and was paired with a transient increase in axonal tension. This indicates that disruption of MT dynamics interferes with neurite outgrowth, not by disrupting the net assembly of MTs at the growth cone, but rather because it alters the balance of forces that power the bulk forward translocation of MTs.

Penetrating Orbital Injury From a Needlefish.

Orbital penetrating injuries are an unfortunately common occurrence; however, those from marine animals are rare. Injuries from marine animals can be quite profound and there are no known reports of complete visual recovery after an orbital penetrating injury. Complications range from secondary infection to a carotid-cavernous fistula, which can complicate the management of these patients. We report a case of penetrating orbital injury from a needlefish with complete return of visual function after surgical removal of foreign debris and an extended course of antibiotics.

Non-Cell-Autonomous Regulation of Retrograde Motoneuronal Axonal Transport in an SBMA Mouse Model.

Defects in axonal transport are seen in motoneuronal diseases, but how that impairment comes about is not well understood. In spinal bulbar muscular atrophy (SBMA), a disorder linked to a CAG/polyglutamine repeat expansion in the androgen receptor (AR) gene, the disease-causing AR disrupts axonal transport by acting in both a cell-autonomous fashion in the motoneurons themselves, and in a non-cell-autonomous fashion in muscle. The non-cell-autonomous mechanism is suggested by data from a unique "myogenic" transgenic (TG) mouse model in which an AR transgene expressed exclusively in skeletal muscle fibers triggers an androgen-dependent SBMA phenotype, including defects in retrograde transport. However, motoneurons in this TG model retain the endogenous AR gene, leaving open the possibility that impairments in transport in this model also depend on ARs in the motoneurons themselves. To test whether non-cell-autonomous mechanisms alone can perturb retrograde transport, we generated male TG mice in which the endogenous AR allele has the testicular feminization mutation (Tfm) and, consequently, is nonfunctional. Males carrying the Tfm allele alone show no deficits in motor function or axonal transport, with or without testosterone treatment. However, when Tfm males carrying the myogenic transgene (Tfm/TG) are treated with testosterone, they develop impaired motor function and defects in retrograde transport, having fewer retrogradely labeled motoneurons and deficits in endosomal flux based on time-lapse video microscopy of living axons. These findings demonstrate that non-cell-autonomous disease mechanisms originating in muscle are sufficient to induce defects in retrograde transport in motoneurons.

Slipping the knot: a comparison of knots used in adjustable suture strabismus surgery.

PURPOSE: To evaluate the frictional force created by different knots used in adjustable suture strabismus surgery. METHODS: To allow the simulation of strabismus surgery suture tying methods a model using 6-0 polyglactin 910 suture was created. Three different knots were evaluated: (1) the sliding noose knot with a double wrap of suture, (2) the cinch knot with a single throw on both sides of the pole suture, (2) and a single-throw square knot. (Bow-tie knots were not included.) A digital force meter was used to measure the force (gram-force [gf]) required to overcome the static friction created by the knot. Each simulation was repeated with new suture material 5 times and the force required after subsequent repositioning was also recorded. RESULTS: The force to overcome static friction of the sliding noose knot was 240 gf [95% CI, 187-284 gf]; of the cinch knot, 150 gf [95% CI, 123-167 gf]; and of the square knot, 110 gf [95% CI, 95-121 gf]. Subsequent movement of each knot along the same suture required progressively less force, with the sliding noose maintaining the most static friction. CONCLUSIONS: The sliding noose knot generates the most frictional force and also maintains the most friction after subsequent repositioning. Important consideration should be given to multiple repositioning movements, because the force required for each subsequent repositioning decreases.