Saltatory Conduction along Myelinated Axons Involves a Periaxonal Nanocircuit.

The propagation of electrical impulses along axons is highly accelerated by the myelin sheath and produces saltating or "jumping" action potentials across internodes, from one node of Ranvier to the next. The underlying electrical circuit, as well as the existence and role of submyelin conduction in saltatory conduction remain, however, elusive. Here, we made patch-clamp and high-speed voltage-calibrated optical recordings of potentials across the nodal and internodal axolemma of myelinated neocortical pyramidal axons combined with electron microscopy and experimentally constrained cable modeling. Our results reveal a nanoscale yet conductive periaxonal space, incompletely sealed at the paranodes, which separates the potentials across the low-capacitance myelin sheath and internodal axolemma. The emerging double-cable model reproduces the recorded evolution of voltage waveforms across nodes and internodes, including rapid nodal potentials traveling in advance of attenuated waves in the internodal axolemma, revealing a mechanism for saltation across time and space.

Left-right symmetry of zebrafish embryos requires somite surface tension.

The body axis of vertebrate embryos is periodically segmented into bilaterally symmetric pairs of somites1,2. The anteroposterior length of somites, their position and left-right symmetry are thought to be molecularly determined before somite morphogenesis3,4. Here we show that, in zebrafish embryos, initial somite anteroposterior lengths and positions are imprecise and, consequently, many somite pairs form left-right asymmetrically. Notably, these imprecisions are not left unchecked and we find that anteroposterior lengths adjust within an hour after somite formation, thereby increasing morphological symmetry. We find that anteroposterior length adjustments result entirely from changes in somite shape without change in somite volume, with changes in anteroposterior length being compensated by corresponding changes in mediolateral length. The anteroposterior adjustment mechanism is facilitated by somite surface tension, which we show by comparing in vivo experiments and in vitro single-somite explant cultures using a mechanical model. Length adjustment is inhibited by perturbation of molecules involved in surface tension, such as integrin and fibronectin. By contrast, the adjustment mechanism is unaffected by perturbations to the segmentation clock, therefore revealing a distinct process that influences morphological segment lengths. We propose that tissue surface tension provides a general mechanism to adjust shapes and ensure precision and symmetry of tissues in developing embryos.

International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials.

PURPOSE: Complications associated with intravitreal anti-VEGF therapies are reported inconsistently in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN: Systematic review and Delphi consensus process. PARTICIPANTS: Twenty-five international retinal specialists participated in the Delphi consensus survey. METHODS: A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to refine the final classification system. MAIN OUTCOME MEASURES: The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS: After screening 18 229 articles, 130 complications were categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. CONCLUSIONS: Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Ductile-to-brittle transition and yielding in soft amorphous materials: perspectives and open questions.

Soft amorphous materials are viscoelastic solids ubiquitously found around us, from clays and cementitious pastes to emulsions and physical gels encountered in food or biomedical engineering. Under an external deformation, these materials undergo a noteworthy transition from a solid to a liquid state that reshapes the material microstructure. This yielding transition was the main theme of a workshop held from January 9 to 13, 2023 at the Lorentz Center in Leiden. The manuscript presented here offers a critical perspective on the subject, synthesizing insights from the various brainstorming sessions and informal discussions that unfolded during this week of vibrant exchange of ideas. The result of these exchanges takes the form of a series of open questions that represent outstanding experimental, numerical, and theoretical challenges to be tackled in the near future.

OCTess: AN OPTICAL CHARACTER RECOGNITION ALGORITHM FOR AUTOMATED DATA EXTRACTION OF SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY REPORTS.

PURPOSE: Manual extraction of spectral domain optical coherence tomography (SD-OCT) reports is time and resource intensive. This study aimed to develop an optical character recognition (OCR) algorithm for automated data extraction from Cirrus SD-OCT macular cube reports. METHODS: SD-OCT monocular macular cube reports (n = 675) were randomly selected from a single-center database of patients from 2020 to 2023. Image processing and bounding box operations were performed, and Tesseract (an OCR library) was used to develop the algorithm, OCTess. The algorithm was validated using a separate test data set. RESULTS: The long short-term memory deep learning version of Tesseract achieved the best performance. After reverifying all discrepancies between human and algorithmic data extractions, OCTess achieved accuracies of 100.00% and 99.98% in the training (n = 125) and testing (n = 550) datasets, while the human error rate was 1.11% (98.89% accuracy) and 0.49% (99.51% accuracy) in each, respectively. OCTess extracted data in 3.1 seconds, compared with 94.3 seconds per report for human evaluators. CONCLUSION: We developed an OCR and machine learning algorithm that extracted SD-OCT data with near-perfect accuracy, outperforming humans in both accuracy and efficiency. This algorithm can be used for efficient construction of large-scale SD-OCT data sets for researchers and clinicians.

SURGICAL DRAINAGE METHODS DURING PARS PLANA VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT: A Systematic Review and Meta-Analysis.

PURPOSE: To assess efficacy and safety outcomes of subretinal fluid drainage methods during pars plana vitrectomy for rhegmatogenous retinal detachment. METHODS: A systematic search strategy was conducted for studies published between January 2000 and October 2022. Included studies reported on either the safety or efficacy of two or more drainage methods during pars plana vitrectomy for patients with rhegmatogenous retinal detachment. RESULTS: Two randomized and five observational studies consisting of 1,524 eyes were included. Best-corrected visual acuity at the last study observation and primary reattachment rates were similar across groups. A significantly lower risk of epiretinal membrane formation was associated with draining subretinal fluid through preexisting retinal breaks (risk ratio = 0.70, 95% confidence interval = [0.60, 0.83], P = <0.01, I 2 = 0%) or with perfluorocarbon liquid (risk ratios = 0.70, 95% confidence interval = [0.59, 0.83], P = <0.01, I 2 = 0%) compared with posterior retinotomy. The risk of an abnormal foveal contour was significantly greater in perfluorocarbon liquid-treated eyes relative to posterior retinotomy (risk ratios = 1.56, 95% confidence interval = [1.13, 2.17], P = <0.01, I 2 = 0%). CONCLUSION: No significant differences were observed in the final best-corrected visual acuity at the last study observation and primary reattachment rates across different drainage methods. There remains limited information on the topic, so future research is warranted.

PARS PLANA VITRECTOMY WITH OR WITHOUT INTERNAL LIMITING MEMBRANE PEEL FOR MACULAR HOLE: A Systematic Review and Meta-Analysis.

PURPOSE: To compare the efficacy and safety of pars plana vitrectomy with and without internal limiting membrane (ILM) peeling for macular hole (MH). METHODS: A systematic literature search on Ovid MEDLINE, Embase, Cochrane Library, and Google Scholar was performed from January 2000 to 2023. The primary outcome was the final best-corrected visual acuity (BCVA). Secondary outcomes included MH closure rates and the need for repeat surgery. The authors performed a random-effects meta-analysis on Review Manager 5.4. RESULTS: Fourteen studies on 880 eyes were included. Pars plana vitrectomy with and without ILM peel achieved a similar final BCVA ( P = 0.66). However, pars plana vitrectomy without ILM peeling achieved a significantly better final BCVA in eyes with closed MHs (WMD = 0.05 logMAR, 95% CI, 0.01-0.10, P = 0.02). Pars plana vitrectomy with ILM peeling achieved a significantly higher primary MH closure rate (RR = 1.21, 95% CI, 1.04-1.42, P = 0.02) and lower incidence of MH reoperation (RR = 0.19, 95% CI, 0.11-0.33, P < 0.001). The final MH closure rate ( P = 0.12) and incidence of MH recurrence ( P = 0.25) were similar between groups. CONCLUSION: Pars plana vitrectomy with and without ILM peel achieved a similar final BCVA. However, pars plana vitrectomy without ILM peeling achieved a better final BCVA in eyes with closed MHs. ILM peeling achieved a greater primary MH closure rate and reduced need for reoperation.

ARTIFICIAL INTELLIGENCE-ENHANCED ANALYSIS OF RETINAL VASCULATURE IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate associations between quantitative vascular measurements derived from intravenous fluorescein angiography (IVFA) and baseline characteristics on optical coherence tomography (OCT) in neovascular age-related macular degeneration (nAMD) patients. METHODS: The authors prospectively recruited patients with active choroidal neovascularization secondary to AMD over 50 years old, presenting to a single center in Toronto, Canada from 2017 to 2023. Ultra-widefield IVFA images were processed using the artificial intelligence RETICAD FAassist system to extract quantitative information on blood flow, perfusion, and blood-retinal-barrier (BRB) permeability. Associations between IVFA parameters with functional and anatomical outcomes were examined using univariable and multivariable regression models. RESULTS: Eighty-one nAMD eyes and seven healthy control eyes were included. Compared with healthy controls, BRB permeability in the central and peripheral retina was significantly higher in nAMD patients (P < 0.001). On univariable analysis, BRB permeability measured centrally was significantly associated with central macular thickness (P = 0.035), whereas perfusion and blood flow measured centrally were significantly associated with macular volume (P = 0.043 and 0.037, respectively). On multivariable analysis, BRB permeability remained significantly associated with central macular thickness (P = 0.026). CONCLUSION: Central BRB permeability measured on IVFA was significantly associated with baseline central macular thickness in nAMD patients. Future work should longitudinally explore associations between IVFA parameters and clinical characteristics in diverse nAMD populations.

ASSOCIATION OF INTRAVENOUS FLUORESCEIN ANGIOGRAPHY AND ADAPTIVE OPTICS IMAGING IN DIABETIC RETINOPATHY: A Prospective Case Series.

PURPOSE: To our knowledge, we present the first case series investigating the relationship between adaptive optics (AO) imaging and intravenous fluorescein angiography (IVFA) parameters in patients with diabetic retinopathy. METHODS: Consecutive patients with diabetic retinopathy older than age 18 years presenting to a single center in Toronto, Canada, from 2020 to 2021 were recruited. Adaptive optics was performed with the RTX1 camera (Imagine Eyes, Orsay, France) at retinal eccentricities of 2° and 4°. Intravenous fluorescein angiography was assessed with the artificial intelligence-based RETICAD system to extract blood flow, perfusion, and blood-retinal-barrier (BRB) permeability at the same retinal locations. Correlations between AO and IVFA parameters were calculated using Pearson's correlation coefficient. RESULTS: Across nine cases, a significant positive correlation existed between photoreceptor spacing on AO and BRB permeability (r = 0.303, P = 0.027), as well as perfusion (r = 0.272, P = 0.049) on IVFA. When stratified by location, a significant positive correlation between photoreceptor dispersion and both BRB permeability and perfusion (r = 0.770, P = 0.043; r = 0.846, P = 0.034, respectively) was observed. Cone density was also negatively correlated with BRB permeability (r = -0.819, P = 0.046). CONCLUSION: Photoreceptor spacing on AO was significantly correlated with BRB permeability and perfusion on IVFA in patients with diabetic retinopathy. Future studies with larger sample sizes are needed to understand the relationship between AO and IVFA parameters in diverse patient populations.

ADAPTIVE OPTICS IMAGING IN DIABETIC RETINOPATHY: A Prospective Cohort Study.

PURPOSE: To investigate the correlation between diabetic retinopathy (DR) severity and microscopic retinal and vascular alterations using adaptive optics imaging. METHODS: In this single-center, prospective cohort study, adult participants with healthy eyes or DR underwent adaptive optics imaging. Participants were classified into control/mild nonproliferative DR, moderate/severe nonproliferative DR, and proliferative DR. Adaptive optics imaging using the RTX1 camera was obtained from 48 participants (87 eyes) for photoreceptor data and from 36 participants (62 eyes) for vascular data. RESULTS: Photoreceptor parameters significantly differed between DR groups at 2° and 4° of retinal eccentricity. Wall-to-lumen ratio varied significantly at 2° eccentricity, while other vascular parameters remained nonsignificant. Cone density and dispersion were the strongest predictors for DR severity ( P < 0.001) in multivariable generalized estimating equation modeling, while other vascular parameters remained nonsignificant between DR severity groups. All photoreceptor parameters showed significant correlations with visual acuity overall and across most DR severity groups. CONCLUSION: To date, this is one of the largest studies evaluating the use of adaptive optics imaging in DR. Adaptive optics imaging was demonstrated to differentiate between various levels of disease severity in DR. These results support the potential role in diagnostic and therapeutic microstructural evaluation in research and clinical practice.

THE ABILITY OF ARTIFICIAL INTELLIGENCE CHATBOTS ChatGPT AND GOOGLE BARD TO ACCURATELY CONVEY PREOPERATIVE INFORMATION FOR PATIENTS UNDERGOING OPHTHALMIC SURGERIES.

INTRODUCTION: To determine whether the two popular artificial intelligence chatbots, ChatGPT and Bard, can provide high-quality information concerning procedure description, risks, benefits, and alternatives of various ophthalmic surgeries. METHODS: ChatGPT and Bard were prompted with questions pertaining to the description, potential risks, benefits, alternatives, and implications of not proceeding with various surgeries in different subspecialties of ophthalmology. Six common ophthalmic procedures were included in the authors' analysis. Two comprehensive ophthalmologists and one subspecialist graded each response independently using a 5-point Likert scale. RESULTS: Likert grading for accuracy was significantly higher for ChatGPT in comparison with Bard (4.5 ± 0.6 vs. 3.8 ± 0.8, P < 0.0001). Generally, ChatGPT performed better than Bard even when questions were stratified by the type of ophthalmic surgery. There was no significant difference between ChatGPT and Bard for response length (2,104.7 ± 271.4 characters vs. 2,441.0 ± 633.9 characters, P = 0.12). ChatGPT responded significantly slower than Bard (46.0 ± 3.0 vs. 6.6 ± 1.2 seconds, P < 0.0001). CONCLUSION: Both ChatGPT and Bard may offer accessible and high-quality information relevant to the informed consent process for various ophthalmic procedures. Nonetheless, both artificial intelligence chatbots overlooked the probability of adverse events, hence limiting their potential and introducing patients to information that may be difficult to interpret.

The Association between Retinal Thickness Fluctuations and Visual Outcomes under Anti-Vascular Endothelial Growth Factor Therapy: A Systematic Review and Meta-Analysis.

INTRODUCTION: The objective of this study was to examine the association between retinal thickness (RT) fluctuations and best corrected visual acuity (BCVA) in eyes with neovascular AMD, macular edema secondary to RVO, and DME treated with anti-VEGF therapy. METHODS: A systematic search of Ovid MEDLINE, EMBASE, and the Cochrane Library was performed from January 2006 to March 2024. Studies comparing visual or anatomic outcomes of patients treated with anti-VEGF therapy, stratified by magnitudes of RT fluctuation, were included. ROBINS-I and Cochrane RoB 2 tools were used to assess risk of bias, and certainty of evidence was evaluated with GRADE criteria. Meta-analysis was performed with a random-effects model. Primary outcomes were final BCVA and change in BCVA relative to baseline. RESULTS: 15,725 articles were screened; 15 studies were identified in the systematic review and 5 studies were included in the meta-analysis. Final ETDRS VA was significantly worse in eyes with the highest level of RT fluctuation (weighted mean difference [WMD] = 7.86 letters; 95% CI, 4.97, 10.74; p < 0.00001; I2 = 81%; 3,136 eyes). RT at last observation was significantly greater in eyes with high RT fluctuations (WMD = -27.35 µm; 95% CI, -0.04, 54.75; p = 0.05; I2 = 88%; 962 eyes). CONCLUSIONS: Final visual outcome is associated with magnitude of RT fluctuation over the course of therapy. It is unclear whether minimizing RT fluctuations would help optimize visual outcomes in patients treated with anti-VEGF therapy. These findings are limited by a small set of studies, risk of bias, and considerable heterogeneity.

Intravitreal Triamcinolone Acetonide for Diabetic Macular Edema and Macular Edema Secondary to Retinal Vein Occlusion: A Meta-Analysis.

BACKGROUND: The comparative safety and efficacy of different doses of intravitreal triamcinolone acetonide (IVTA) for diabetic macular edema (DME) and macular edema (ME) secondary to retinal vein occlusion (RVO) is unclear. OBJECTIVES: This meta-analysis aimed to compare the safety and efficacy of different doses of IVTA in this setting. METHODS: A systematic literature search for randomized clinical trials (RCTs) was conducted on Cochrane Library, Ovid MEDLINE, and EMBASE from January 2005 to May 2022. Studies that reported on patients with DME or ME secondary to RVO that received treatment with different doses of IVTA were included. A random-effects meta-analysis was performed. Cochrane's Risk of Bias Tool 2 was used to assess the risk of bias, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines were used to assess certainty of evidence. RESULTS: Five RCTs reporting on 1,041 eyes at baseline were included in this meta-analysis. In eyes with ME secondary to RVO, high-dose (4 mg) IVTA achieved a significantly better change in best-corrected visual acuity (WMD = -4.75 ETDRS letters, 95% CI = [-7.73, -1.78], p = 0.002) and reduction in retinal thickness (WMD = -93.02 µm, 95% CI = [-153.23, -32.82], p = 0.002) at months 4-6 compared to low-dose (1-2 mg) IVTA. However, high-dose IVTA had a higher risk of intraocular pressure-related adverse events (RR = 2.99, 95% CI = [1.05, 8.50], p = 0.04) and cataract surgery (RR = 5.67, 95% CI = [3.09, 10.41], p < 0.00001) than low-dose IVTA in eyes with ME secondary to RVO. These efficacy and safety differences in high-dose and low-dose IVTA were not observed in DME eyes. CONCLUSIONS: The RCT evidence in this setting is limited. High-dose IVTA achieved greater improvements in visual acuity and reductions in retinal thickness than low-dose IVTA at months 4-6. However, high-dose IVTA had a less favorable safety profile than low-dose IVTA. The significance of these outcomes was based on patients with ME secondary to RVO, but not DME.

Pars Plana Vitrectomy with or without Internal Limiting Membrane Peel for Epiretinal Membrane: A Systematic Review and Meta-Analysis.

BACKGROUND: The safety and effectiveness of pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling remains poorly understood for the treatment of epiretinal membrane (ERM). OBJECTIVES: Our study aims to compare the safety and effectiveness of PPV with and without ILM peeling for ERM. METHODS: A systematic literature search was conducted on Ovid MEDLINE, Embase, Cochrane Library, and Google Scholar from January 2000 to January 2023 for comparative studies reporting visual and anatomical outcomes for patients with ERM that received PPV with or without ILM peeling. Primary outcomes included best-corrected visual acuity (BCVA) at last study observation and change in BCVA from baseline. Secondary outcomes included retinal thickness (RT) at last study observation, change in RT from baseline, risk of ERM recurrence, and adverse events. A random-effects meta-analysis was performed. Risk of bias of randomized controlled trials was assessed using the Risk of Bias 2 tool of observational studies using the Risk of Bias in Non-randomized Studies of Interventions-I tool. The certainty of evidence of outcomes was evaluated using Grading of Recommendations, Assessment, Development and Evaluation criteria. RESULTS: Nineteen studies reporting on 1,291 eyes at baseline were included. PPV with and without ILM peel achieved a similar BCVA at last study observation (p = 0.68) and change in BCVA from baseline (p = 0.79). These findings remained consistent irrespective of whether simultaneous phacoemulsification was performed. PPV with ILM peel achieved a significantly lower incidence of ERM recurrence (risk ratio [RR] = 0.26, 95% CI = [0.13, 0.51], p < 0.0001) and additional surgery (RR = 0.17, 95% CI = [0.04, 0.74], p = 0.02) compared to PPV without ILM peel. CONCLUSION: PPV with and without ILM peel achieved a similar BCVA at last study observation in ERM patients. Patients treated with PPV and ILM peel also had a reduced risk of ERM recurrence and lower reoperation risk. These conclusions are associated with a moderate certainty of evidence and potential for bias from multiple non-randomized studies.

Epiretinal Membrane Formation following Rhegmatogenous Retinal Detachment Repair: A Retrospective Cohort Study.

INTRODUCTION: This study aimed to investigate the incidence of and risk factors for epiretinal membrane (ERM) formation following primary rhegmatogenous retinal detachment (RRD) repair. METHODS: This comparative, retrospective, single-center cohort study included eyes with primary RRD treated between 2011 and 2023 at Massachusetts Eye and Ear, Boston, Massachusetts, with pars plana vitrectomy (PPV), scleral buckle (SB), PPV+SB, or pneumatic retinopexy (PnR). Demographic, clinical, and surgical parameters were collected from medical records. The primary outcome was the risk of ERM formation, while the secondary outcome was the risk of ERM requiring surgery. Univariable and multivariable Cox regression were performed, and a hazard ratio (HR) and 95% confidence interval (95% CI) were reported. RESULTS: Overall, 394 eyes were included. The mean age was 58.49 ± 12.8 years, and most patients were male. There was a significantly lower risk of ERM formation following SB compared to PPV in the univariable analysis (HR = 0.2, 95% CI = 0.08-0.60, p = 0.003); however, there was no significant association between treatment modality and ERM formation on multivariable Cox regression controlling for confounding factors (p = 0.24). ERM formation was found more commonly in patients who were older (HR = 1.0 per 1 year increase in age, 95% CI = 1.01-1.04, p = 0.001), those with worse baseline visual acuity (HR = 1.3, 95% CI = 1.09-1.71, p = 0.008), and those with macula-off RRDs (HR = 2.1, 95% CI = 1.41-3.32, p < 0.001). CONCLUSION: Surgical modality does not have a significant impact on the risk of ERM following retinal detachment repair. However, age, baseline visual acuity, and macular status are important predictors of ERM formation after RRD repair.

ChatGPT-4: An assessment of an upgraded artificial intelligence chatbot in the United States Medical Licensing Examination.

PURPOSE: ChatGPT-4 is an upgraded version of an artificial intelligence chatbot. The performance of ChatGPT-4 on the United States Medical Licensing Examination (USMLE) has not been independently characterized. We aimed to assess the performance of ChatGPT-4 at responding to USMLE Step 1, Step 2CK, and Step 3 practice questions. METHOD: Practice multiple-choice questions for the USMLE Step 1, Step 2CK, and Step 3 were compiled. Of 376 available questions, 319 (85%) were analyzed by ChatGPT-4 on March 21st, 2023. Our primary outcome was the performance of ChatGPT-4 for the practice USMLE Step 1, Step 2CK, and Step 3 examinations, measured as the proportion of multiple-choice questions answered correctly. Our secondary outcomes were the mean length of questions and responses provided by ChatGPT-4. RESULTS: ChatGPT-4 responded to 319 text-based multiple-choice questions from USMLE practice test material. ChatGPT-4 answered 82 of 93 (88%) questions correctly on USMLE Step 1, 91 of 106 (86%) on Step 2CK, and 108 of 120 (90%) on Step 3. ChatGPT-4 provided explanations for all questions. ChatGPT-4 spent 30.8 ± 11.8 s on average responding to practice questions for USMLE Step 1, 23.0 ± 9.4 s per question for Step 2CK, and 23.1 ± 8.3 s per question for Step 3. The mean length of practice USMLE multiple-choice questions that were answered correctly and incorrectly by ChatGPT-4 was similar (difference = 17.48 characters, SE = 59.75, 95%CI = [-100.09,135.04], t = 0.29, p = 0.77). The mean length of ChatGPT-4's correct responses to practice questions was significantly shorter than the mean length of incorrect responses (difference = 79.58 characters, SE = 35.42, 95%CI = [9.89,149.28], t = 2.25, p = 0.03). CONCLUSIONS: ChatGPT-4 answered a remarkably high proportion of practice questions correctly for USMLE examinations. ChatGPT-4 performed substantially better at USMLE practice questions than previous models of the same AI chatbot.

Random Traction Yielding Transition in Epithelial Tissues.

We investigate how randomly oriented cell traction forces lead to fluidization in a vertex model of epithelial tissues. We find that the fluidization occurs at a critical value of the traction force magnitude F_{c}. We show that this transition exhibits critical behavior, similar to the yielding transition of sheared amorphous solids. However, we find that it belongs to a different universality class, even though it satisfies the same scaling relations between critical exponents established in the yielding transition of sheared amorphous solids. Our work provides a fluidization mechanism through active force generation that could be relevant in biological tissues.

Effectiveness of oral versus intravenous tranexamic acid in primary total hip and knee arthroplasty: a randomised, non-inferiority trial.

BACKGROUND: Tranexamic acid (TXA) reduces rates of blood transfusion for total hip arthroplasty (THA) and total knee arthroplasty (TKA). Although the use of oral TXA rather than intravenous (i.v.) TXA might improve safety and reduce cost, it is not clear whether oral administration is as effective. METHODS: This noninferiority trial randomly assigned consecutive patients undergoing primary THA or TKA under neuraxial anaesthesia to either one preoperative dose of oral TXA or one preoperative dose of i.v. TXA. The primary outcome was calculated blood loss on postoperative day 1. Secondary outcomes were transfusions and complications within 30 days of surgery. RESULTS: Four hundred participants were randomised (200 THA and 200 TKA). The final analysis included 196 THA patients (98 oral, 98 i.v.) and 191 TKA patients (93 oral, 98 i.v.). Oral TXA was non-inferior to i.v. TXA in terms of calculated blood loss for both THA (effect size=-18.2 ml; 95% confidence interval [CI], -113 to 76.3; P<0.001) and TKA (effect size=-79.7 ml; 95% CI, -178.9 to 19.6; P<0.001). One patient in the i.v. TXA group received a postoperative transfusion. Complication rates were similar between the two groups (5/191 [2.6%] oral vs 5/196 [2.6%] i.v.; P=1.00). CONCLUSIONS: Oral TXA can be administered in the preoperative setting before THA or TKA and performs similarly to i.v. TXA with respect to blood loss and transfusion rates. Switching from i.v. to oral TXA in this setting has the potential to improve patient safety and decrease costs.

Maximal Extension Interval and Visual Outcomes in a Treat-and-Extend Protocol: A Post Hoc Analysis of the CANTREAT Randomized Trial.

INTRODUCTION: The Canadian Treat-and-Extend Analysis Trial with Ranibizumab (CANTREAT) was a 2-year, multicentred, randomized clinical trial to evaluate treat-and-extend (T&E) relative to monthly administration of ranibizumab in neovascular age-related macular degeneration (nAMD). This post hoc analysis of the CANTREAT trial explores the relationship between the maximal extension interval tolerated by patients receiving T&E ranibizumab and visual acuity outcomes. METHODS: Treatment-naïve patients with nAMD were randomized to receive either a once-monthly dosing or T&E regimen of ranibizumab across 27 treatment centres in Canada and were followed for 24 months. For this post hoc analysis, patients in the T&E cohort were subdivided into the following groups based on maximum extension interval: 4 weeks, 6 weeks, 8 weeks, 10 weeks, and 12 weeks. The primary outcome was the change in ETDRS best-corrected visual acuity (BCVA) from baseline to month 24 while secondary outcomes included change in central retinal thickness (CRT). All results were reported using descriptive statistics. RESULTS: A total of 285 participants undergoing T&E were enrolled in this post hoc analysis. At month 24, the change in BCVA from baseline was +8.5 ± 9.3, +7.7 ± 13.8, +4.4 ± 9.6, +4.4 ± 18.5, and +7.8 ± 14.8 letters in the 4-, 6-, 8-, 10-, and 12-week cohorts, respectively. The change in CRT at month 24 was -79.2 ± 95.0, -143.9 ± 128.9, -97.7 ± 101.1, -120.9 ± 105.3, and -133.2 ± 108.8 µm in the 4-, 6-, 8-, 10-, and 12-week cohorts, respectively. CONCLUSION: The capacity to extend does not necessarily associate with improved visual acuity outcomes, with the poorest change in BCVA seen in those extended 8-10 weeks. The highest change in BCVA and lowest decrease in CRT was in the group maximally extended for 4 weeks. There was a correlation between change in BCVA and change in CRT for other extension groups. Future studies should establish the predictive factors for successful extension in patients undergoing T&E in nAMD.

Anti-Vascular Endothelial Growth Factor Therapy Regimens for Polypoidal Choroidal Vasculopathy: A Systematic Review.

INTRODUCTION: There are no guidelines on the optimal anti-vascular endothelial growth factor (anti-VEGF) monotherapy regimen for patients with polypoidal choroidal vasculopathy (PCV). In this study, we aimed to assess the comparative safety and efficacy of different treatment regimens of anti-VEGF monotherapy for PCV. METHODS: We conducted a systematic literature search on Ovid MEDLINE, Embase, and Cochrane Library from January 2000 to May 2023 for comparative articles reporting on different treatment regimens of anti-VEGF agents in PCV. Our primary outcomes were the final best-corrected visual acuity (BCVA) and the change in BCVA from baseline. Secondary outcomes were the final retinal thickness (RT), the change in RT from baseline, the rate of polyp closure, and the incidence of adverse events. RESULTS: A total of 10,440 studies were screened, and seven studies reporting on 636 eyes with PCV at baseline were included in this systematic review. One RCT of 53 eyes found a similar final BCVA, change in BCVA from baseline, final RT, and complete polyp closure rate between a treat-and-extend (T&E) regimen and a bimonthly fixed-dosing regimen of aflibercept. This trial also found superiority of T&E for change in RT from baseline. One observational study of 33 eyes found a similar BCVA at last study observation between a pro re nata (PRN) regimen and bimonthly fixed-dosing regimen of aflibercept. One observational study of 42 eyes found a similar change in BCVA from baseline and complete polyp closure rate between a PRN regimen and bimonthly fixed-dosing regimen of aflibercept. One RCT of 249 eyes found a similar change in BCVA and RT from baseline, as well as polyp closure, between a T&E regimen and fixed 12-week dosing regimen of conbercept. One observational study of 30 eyes found a superiority of T&E aflibercept for change in BCVA and risk of polyp recurrence, compared to a PRN regimen. CONCLUSION: Overall, there is a paucity of evidence comparing various treatment regimens of anti-VEGF therapy in patients with PCV. This limited evidence suggests that current treatment regimens are similarly efficacious, though T&E aflibercept achieved superior outcomes when compared to bimonthly dosing or PRN in some individual studies. Further trials are needed to confirm or refute these findings.