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Acute kidney injury (AKI) has emerged as a global health crisis, surpassing mortality rates associated with several cancers and heart failure. The lack of effective therapies, coupled with challenges in diagnosis and the high cost of kidney transplantation, underscores the urgent need to explore novel therapeutic targets and strategies for AKI. Understanding the intricate pathophysiology of AKI is paramount in this endeavor. The components of the apelinergic system-namely, apelin and elabela/toddler, along with their receptor-are prominently expressed in various kidney cells and have garnered significant attention in renal research. Recent studies have highlighted the renoprotective role of the apelinergic system in AKI. This system exerts its protective effects by modulating several pathophysiological processes, including reducing endoplasmic reticulum (ER) stress, improving mitochondrial dynamics, inhibiting inflammation and apoptosis, promoting diuresis through vasodilation of renal vasculature, and counteracting the effects of reactive oxygen species (ROS). Despite these advancements, the precise involvement of the apelinergic system in the progression of AKI remains unclear. Furthermore, the therapeutic potential of apelin-13 in AKI is not fully understood. This review aims to elucidate the role of the apelinergic system in AKI and its interactions with key pathomechanisms involved in the progression of AKI. Additionally, we discuss the current clinical status of exogenous apelin-13 therapy, providing insights that will guide future research on apelin against AKI., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A simple lateral dynamic walker, with swing leg dynamics and three adjustable input parameters, is used to study how motor regulation affects frontal-plane stepping. Motivated by experimental observations and phenomenological models, we imposed task-level multi-objective regulation targeting the walker's optimal lateral foot placement at each step. The regulator prioritizes achieving step width and lateral body position goals to varying degrees by choosing a mixture parameter. Our model thus integrates a lateral mechanical template , which captures the fundamental mechanics of frontal-plane walking, with a lateral motor regulation template , an empirically verified model of how humans manipulate lateral foot placements in a goal-directed manner. The model captures experimentally observed stepping fluctuation statistics and demonstrates how linear empirical models of stepping dynamics can emerge from first-principles nonlinear mechanics. We find that task-level regulation gives rise to a goal-equivalent manifold in the system's extended state space of mechanical states and inputs, a subset of which contains a continuum of period-1 gaits forming a semistable set: perturbations off of any of its gaits result in transients that return to the set, though typically to different gaits.

Purpose: Ocular surface disorders (OSDs) can severely affect vision and quality of life. Autologous blood products, such as plasma rich in growth factors (PRGF), are recently available to treat OSDs refractory to traditional therapies. This review aims to summarize the efficacy and safety of PRGF in OSDs., Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was established a priori and published on PROSPERO (CRD42024522119). MEDLINE, Embase, and Cochrane Library were searched for primary articles until February 6, 2024. Primary outcomes included slit-lamp examination findings and patient-reported outcomes. Secondary outcomes included visual outcomes and adverse events. Risk of bias was assessed using the Cochrane Risk of Bias and ROBINS-I tools., Results: Twenty-two studies involving 1158 eyes were included. PRGF showed notable improvement in objective and subjective outcomes in OSDs. Comparative studies did not show PRGF to be superior to a standard steroid taper for dry eye disease. However, the use of PRGF was also reported in persistent epithelial defects and corneal ulcerations. In these conditions, there were high rates of complete healing and reduced corneal staining. PRGF has also been reported to improve ocular surface healing and stability when used as an adjunct to refractive and pterygium surgeries. No serious adverse events were reported., Conclusions: PRGF has potential as an effective treatment of OSDs resistant to traditional therapies with minimal safety concerns. Large randomized controlled trials are needed to better evaluate the role of PRGF within the treatment armamentarium for corneal pathologies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The document emphasizes the importance of addressing key issues in Quality Management Systems (QMS) to stay competitive and provide high-quality goods and services in a dynamic market. It highlights the need to adopt novel quality management techniques for long-term success. The fundamentals of Quality by Design (QbD) are discussed, tracing back to pioneers like Joseph M. Juran and the Six Sigma concept for effective implementation. QbD is described as a systematic approach focusing on risk management, Quality Target Product Profile (QTPP), and Critical Quality Attributes (CQAs) to create products meeting predetermined quality standards. QbD incorporates quality concepts into the development and production processes. Its goal is to guarantee the quality of the product by determining and managing important factors. Manufacturers can be flexible with it while still adhering to strict quality standards. It signifies a change in the industry's paradigm., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Radiology teaching for undergraduate medical students is often limited in amount and lacking a longitudinal approach spanning multiple years. At our institution, we had a goal to develop a formal and sustainable radiology curriculum. There were sequential changes made to the curriculum over several years and here, the successes, challenges, and lessons learned are outlined. Alongside these elements, student radiology quiz results and survey data over several years are also summarized. Curricular development included integrated anatomy and radiology sessions, revamped lectures focusing on interactivity and eliminating unnecessary redundancies across the multi-year curriculum, radiology media files to supplement problem-based learning, clinical skills videos, and a pre-clerkship radiology bootcamp elective., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Purpose: With the popularization of ChatGPT (Open AI, San Francisco, California, United States) in recent months, understanding the potential of artificial intelligence (AI) chatbots in a medical context is important. Our study aims to evaluate Google Gemini and Bard's (Google, Mountain View, California, United States) knowledge in ophthalmology., Methods: In this study, we evaluated Google Gemini and Bard's performance on EyeQuiz, a platform containing ophthalmology board certification examination practice questions, when used from the United States (US). Accuracy, response length, response time, and provision of explanations were evaluated. Subspecialty-specific performance was noted. A secondary analysis was conducted using Bard from Vietnam, and Gemini from Vietnam, Brazil, and the Netherlands., Results: Overall, Google Gemini and Bard both had accuracies of 71% across 150 text-based multiple-choice questions. The secondary analysis revealed an accuracy of 67% using Bard from Vietnam, with 32 questions (21%) answered differently than when using Bard from the US. Moreover, the Vietnam version of Gemini achieved an accuracy of 74%, with 23 (15%) answered differently than the US version of Gemini. While the Brazil (68%) and Netherlands (65%) versions of Gemini performed slightly worse than the US version, differences in performance across the various country-specific versions of Bard and Gemini were not statistically significant., Conclusion: Google Gemini and Bard had an acceptable performance in responding to ophthalmology board examination practice questions. Subtle variability was noted in the performance of the chatbots across different countries. The chatbots also tended to provide a confident explanation even when providing an incorrect answer., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

In this systematic review, the efficacy of scleral buckle (SB) with pars plana vitrectomy (PPV) was compared to PPV alone in eyes with rhegmatogenous retinal detachment (RRD) due to inferior retinal breaks (IRB). Measured outcomes included final best-corrected visual acuity (BCVA), anatomic success, and complication rates in randomized controlled trials and observational studies from 2000 to 2022. Among four studies (696 eyes), three studies demonstrated no significant difference between PPV and PPV/SB for final BCVA, whereas one study reported better BCVA with added SB. PPV/SB yielded comparable single-surgery anatomical success (SSAS) and final anatomical success (FAS) in three studies relative to PPV alone ( P < 0.05); however, one study reported better SSAS with added SB. Stratifying by lens status revealed a SSAS benefit with PPV/SB in phakic eyes ( P = 0.046). No significant difference was seen in complication rates. In conclusion, PPV and PPV/SB were associated with similar functional outcomes and risk profile, whereas SSAS may be improved with PPV/SB in phakic eyes with RRD due to IRB. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.] .

Purpose: Patients may seek online information to better understand medical imaging procedures. The purpose of this study was to assess the accuracy of information provided by 2 popular artificial intelligence (AI) chatbots pertaining to common imaging scenarios' risks, benefits, and alternatives., Methods: Fourteen imaging-related scenarios pertaining to computed tomography (CT) or magnetic resonance imaging (MRI) were used. Factors including the use of intravenous contrast, the presence of renal disease, and whether the patient was pregnant were included in the analysis. For each scenario, 3 prompts for outlining the (1) risks, (2) benefits, and (3) alternative imaging choices or potential implications of not using contrast were inputted into ChatGPT and Bard. A grading rubric and a 5-point Likert scale was used by 2 independent reviewers to grade responses. Prompt variability and chatbot context dependency were also assessed., Results: ChatGPT's performance was superior to Bard's in accurately responding to prompts per Likert grading (4.36 ± 0.63 vs 3.25 ± 1.03 seconds, P  < .0001). There was substantial agreement between independent reviewer grading for ChatGPT (κ = 0.621) and Bard (κ = 0.684). Response text length was not statistically different between ChatGPT and Bard (2087 ± 256 characters vs 2162 ± 369 characters, P  = .24). Response time was longer for ChatGPT (34 ± 2 vs 8 ± 1 seconds, P  < .0001)., Conclusions: ChatGPT performed superior to Bard at outlining risks, benefits, and alternatives to common imaging scenarios. Generally, context dependency and prompt variability did not change chatbot response content. Due to the lack of detailed scientific reasoning and inability to provide patient-specific information, both AI chatbots have limitations as a patient information resource., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: This review consolidates findings from studies that used a preoperative visual acuity (VA) threshold as an indication for epiretinal membrane (ERM) surgery., Methods: The literature was systematically searched using Ovid MEDLINE, EMBASE, and Cochrane Library from January 2000 to October 2022 to select studies reporting on pars plana vitrectomy (PPV) for ERM that used a preoperative VA threshold as an inclusion criterion. Primary outcomes were final best-corrected visual acuity (BCVA) and change in BCVA relative to baseline. Secondary outcomes included risk of intra- and postoperative complications., Results: A total of 639 eyes from seven studies were included. The most liberal preoperative VA threshold was 20/28.5 or worse, whereas the most conservative threshold was worse than 20/60. The mean preoperative BCVA was 0.55 logarithm of the minimum angle of resolution (logMAR) (∼20/70), and the mean postoperative BCVA was 0.35 logMAR (∼20/45). Generally, VA improved relative to baseline, regardless of the preoperative VA threshold. The smallest improvement in VA was observed in a study where the pre-operative VA to consider surgery was liberal (20/30 or worse), whereas the greatest VA improvement was observed in a study that used a conservative preoperative VA threshold (worse than 20/60)., Conclusions: The greatest improvement in BCVA was observed in studies where a conservative pre-operative VA threshold was used. The decision to operate should involve a patient-centered approach with a thorough discussion of the risks and benefits of PPV, regardless of the preoperative VA threshold used. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:400-407.] .

Purpose: To investigate the association between social determinants of health (SDH) in the domains of social and community context, education access, environmental context, economic stability, and healthcare access, with glaucoma prevalence., Design: Cross-sectional study., Methods: The study population consisted of adult participants who answered glaucoma-related questions on the 2017 National Health Interview Survey (NHIS), the most recent iteration that includes glaucoma-related questions. The main outcome measures included the relationships between SDH-related factors and self-reported glaucoma diagnosis as well as self-reported glaucomatous vision loss were examined using univariable and multivariable regression models., Results: In total, 26,696 of 26,742 (99.83%) NHIS respondents were included, of whom 880 (3.30%) reported a glaucoma diagnosis and 275 (1.03%) reported glaucomatous vision loss. Participants were predominantly middle-aged (50.95 ± 18.60 years), female (54.75%), and non-Hispanic White (70.49%). In age-adjusted multivariable regression (n = 25,456), non-Hispanic Black race (odds ratio [OR] = 1.87, 99% CI = [1.37, 2.55], P < .001, compared to non-Hispanic White race) and poor health status (OR = 1.54, 99% CI = [1.00, 2.37], P = .01, compared to good health status) were significant predictors of glaucoma diagnosis. For glaucomatous vision loss, having an income below the poverty threshold (OR = 2.41, 99% CI = [1.12, 5.20], P = .003, compared to income ≥5 times the poverty threshold) was the only significant predictor in univariable analyses. No SDH-related factors were significantly associated with glaucomatous vision loss in multivariable analysis (n = 848). Multicollinearity was minimal (variation inflation factor<1.6 for all independent variables)., Conclusions: Non-Hispanic Black race and poor health status were associated with self-reported glaucoma diagnosis. Physicians and policymakers may consider SDH when assessing clinical risk and designing public health interventions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To elicit associations between vision difficulties and physical or psychosocial challenges in children in the United States., Methods: Children aged 2-17 years old from the 2021 National Health Interview Survey with data pertaining to vision difficulty were included in our retrospective, population-based analysis. Our primary aim was investigating physical and psychosocial challenges as predictors of vision difficulty. Logistic regression models were performed on Stata version 17.0 (StataCorp LLC, College Station, Texas). Analyses were accompanied by an odds ratio (OR) and 95% confidence interval (CI)., Results: A total of 7,373 children had data pertaining to their level of vision difficulty and were included in our sample. In our multivariable analysis, children with a good/fair (OR = 1.84, 95% CI = [1.31, 2.60], p  < 0.01), or poor (OR = 5.08, 95% CI = [1.61, 16.04], p  < 0.01) general health status had higher odds of vision difficulty relative to children with an excellent/very good health status. Furthermore, children with difficulties hearing (OR = 8.67, 95% CI = [5.25, 14.31], p  < 0.01), communicating (OR = 1.96, 95% CI = [1.18, 3.25], p  < 0.01), learning (OR = 1.93, 95% CI = [1.27, 2.93], p  < 0.01), and making friends (OR = 1.94, 95% CI = [1.12, 3.36], p  = 0.02) had higher odds of vision difficulty. Nonetheless, the following factors were only predictors of vision difficulty in our univariable analysis: requiring equipment for mobility ( p  < 0.01), experiencing anxiety ( p  < 0.01), and experiencing depression ( p  < 0.01)., Conclusion: Several factors pertaining to physical and psychosocial challenges in children are associated with vision difficulty. Future research should further explore potential causal links between vision difficulty and physical or psychosocial factors to aid in coordinating public health efforts dedicated to vision health equity.

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.

Cancer immunotherapy has transformed the clinical approach to patients with malignancies, as profound benefits can be seen in a subset of patients. To identify this subset, biomarker analyses increasingly focus on phenotypic and functional evaluation of the tumor microenvironment to determine if density, spatial distribution, and cellular composition of immune cell infiltrates can provide prognostic and/or predictive information. Attempts have been made to develop standardized methods to evaluate immune infiltrates in the routine assessment of certain tumor types; however, broad adoption of this approach in clinical decision-making is still missing. We developed approaches to categorize solid tumors into 'desert', 'excluded', and 'inflamed' types according to the spatial distribution of CD8+ immune effector cells to determine the prognostic and/or predictive implications of such labels. To overcome the limitations of this subjective approach, we incrementally developed four automated analysis pipelines of increasing granularity and complexity for density and pattern assessment of immune effector cells. We show that categorization based on 'manual' observation is predictive for clinical benefit from anti-programmed death ligand 1 therapy in two large cohorts of patients with non-small cell lung cancer or triple-negative breast cancer. For the automated analysis we demonstrate that a combined approach outperforms individual pipelines and successfully relates spatial features to pathologist-based readouts and the patient's response to therapy. Our findings suggest that tumor immunophenotype generated by automated analysis pipelines should be evaluated further as potential predictive biomarkers for cancer immunotherapy. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)

Objective: To compare intraoperative hemodynamic parameters, blood loss, renal function, and duration of surgery with and without temporary portocaval shunt (TPCS) in live donor liver transplantation (LT) recipients. Secondary objectives were postoperative early graft dysfunction, morbidity, mortality, total intensive care unit, and hospital stay., Background: Blood loss during recipient hepatectomy for LT remains a major concern. Routine use of TPCS during LT is not yet elucidated., Methods: This study is a single-center, open-label, randomized control trial. The sample size was calculated based on intraoperative blood loss. After exclusion, a total of 60 patients, 30 in each arm (TPCS vs no TPCS) were recruited in the trial., Results: The baseline recipient and donor characteristics were comparable between the groups. The median intraoperative blood loss ( P = 0.004) and blood product transfusions ( P < 0.05) were significantly less in the TPCS group. The TPCS group had significantly improved intraoperative hemodynamics in the anhepatic phase as compared with the no TPCS group ( P < 0.0001), requiring significantly less vasopressor support. This led to significantly better renal function as evidenced by higher intraoperative urine output in the TPCS group ( P = 0.002). Because of technical simplicity, the TPCS group had significantly fewer inferior vena cava injuries (3.3 vs 26.7%, P = 0.026) and substantially shorter hepatectomy time and total duration of surgery (529.4 ± 35.54 vs 606.83 ± 48.13 min, P < 0.0001). The time taken for normalization of lactate in the immediate postoperative period was significantly shorter in the TPCS group (median, 6 vs 13 h; P = 0.04). Although postoperative endotoxemia, major morbidity, 90-day mortality, total intensive care unit, and hospital stay were comparable between both groups, tolerance to enteral feed was earlier in the TPCS group., Conclusions: In live donor LT, TPCS is a simple and effective technique that provides superior intraoperative hemodynamics and reduces blood loss and duration of surgery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Bard by Google, a direct competitor to ChatGPT, was recently released. Understanding the relative performance of these different chatbots can provide important insight into their strengths and weaknesses as well as which roles they are most suited to fill. In this project, we aimed to compare the most recent version of ChatGPT, ChatGPT-4, and Bard by Google, in their ability to accurately respond to radiology board examination practice questions., Methods: Text-based questions were collected from the 2017-2021 American College of Radiology's Diagnostic Radiology In-Training (DXIT) examinations. ChatGPT-4 and Bard were queried, and their comparative accuracies, response lengths, and response times were documented. Subspecialty-specific performance was analyzed as well., Results: 318 questions were included in our analysis. ChatGPT answered significantly more accurately than Bard (87.11% vs 70.44%, P < .0001). ChatGPT's response length was significantly shorter than Bard's (935.28 ± 440.88 characters vs 1437.52 ± 415.91 characters, P < .0001). ChatGPT's response time was significantly longer than Bard's (26.79 ± 3.27 seconds vs 7.55 ± 1.88 seconds, P < .0001). ChatGPT performed superiorly to Bard in neuroradiology, (100.00% vs 86.21%, P = .03), general & physics (85.39% vs 68.54%, P < .001), nuclear medicine (80.00% vs 56.67%, P < .01), pediatric radiology (93.75% vs 68.75%, P = .03), and ultrasound (100.00% vs 63.64%, P < .001). In the remaining subspecialties, there were no significant differences between ChatGPT and Bard's performance., Conclusion: ChatGPT displayed superior radiology knowledge compared to Bard. While both chatbots display reasonable radiology knowledge, they should be used with conscious knowledge of their limitations and fallibility. Both chatbots provided incorrect or illogical answer explanations and did not always address the educational content of the question., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Ophthalmology is reliant on effective interpretation of multimodal imaging to ensure diagnostic accuracy. The new ability of ChatGPT-4 (OpenAI) to interpret ophthalmic images has not yet been explored., Objective: To evaluate the performance of the novel release of an artificial intelligence chatbot that is capable of processing imaging data., Design, Setting, and Participants: This cross-sectional study used a publicly available dataset of ophthalmic cases from OCTCases, a medical education platform based out of the Department of Ophthalmology and Vision Sciences at the University of Toronto, with accompanying clinical multimodal imaging and multiple-choice questions. Across 137 available cases, 136 contained multiple-choice questions (99%)., Exposures: The chatbot answered questions requiring multimodal input from October 16 to October 23, 2023., Main Outcomes and Measures: The primary outcome was the accuracy of the chatbot in answering multiple-choice questions pertaining to image recognition in ophthalmic cases, measured as the proportion of correct responses. χ2 Tests were conducted to compare the proportion of correct responses across different ophthalmic subspecialties., Results: A total of 429 multiple-choice questions from 136 ophthalmic cases and 448 images were included in the analysis. The chatbot answered 299 of multiple-choice questions correctly across all cases (70%). The chatbot's performance was better on retina questions than neuro-ophthalmology questions (77% vs 58%; difference = 18%; 95% CI, 7.5%-29.4%; χ21 = 11.4; P < .001). The chatbot achieved a better performance on nonimage-based questions compared with image-based questions (82% vs 65%; difference = 17%; 95% CI, 7.8%-25.1%; χ21 = 12.2; P < .001).The chatbot performed best on questions in the retina category (77% correct) and poorest in the neuro-ophthalmology category (58% correct). The chatbot demonstrated intermediate performance on questions from the ocular oncology (72% correct), pediatric ophthalmology (68% correct), uveitis (67% correct), and glaucoma (61% correct) categories., Conclusions and Relevance: In this study, the recent version of the chatbot accurately responded to approximately two-thirds of multiple-choice questions pertaining to ophthalmic cases based on imaging interpretation. The multimodal chatbot performed better on questions that did not rely on the interpretation of imaging modalities. As the use of multimodal chatbots becomes increasingly widespread, it is imperative to stress their appropriate integration within medical contexts.

Background: The efficacy and safety of initial tap and inject (T/I) compared with pars plana vitrectomy (PPV) for acute postoperative bacterial endophthalmitis following cataract surgery is unclear. Understanding the comparative safety and efficacy of initial T/I and initial PPV can provide context for treatment decision making in this setting., Methods: A systematic literature search was performed on Ovid MEDLINE, EMBASE, and the Cochrane Library from January 1990 to January 2021. Comparative studies reporting on final best-corrected visual acuity (BCVA) following initial T/I or PPV in patients with infectious endophthalmitis secondary to cataract surgery were included. Cochrane's Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) was used to evaluate the risk of bias, and GRADE criteria were used to assess certainty of evidence. A random-effects model was used for meta-analysis., Results: Seven nonrandomized studies reporting on 188 eyes at baseline were included in this meta-analysis. Initial T/I achieved a significantly better BCVA at last study observation than initial PPV (weighted mean difference [WMD] = -0.61 logMAR; 95% CI, -1.19 to -0.03; p = 0.04; I 2  = 89%; n = 7 studies; GRADE = very low). The incidence of enucleation was similar between initial T/I and initial PPV (risk ratio [RR] = 0.73; 95% CI, 0.09-6.25; p = 0.78; I 2  = 4%; n = 2 studies; GRADE = very low). The risk of retinal detachment was similar between treatment modalities (RR = 0.29; 95% CI, 0.01-5.94; p = 0.42; I 2  = 52%; n = 2 studies; GRADE = very low)., Conclusions: The quality of evidence in this setting is limited. T/I had a significantly better BCVA at last study observation than initial PPV. Safety profiles were similar between T/I and PPV., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To review current eyedrop instillation techniques, common difficulties faced by patients instilling eyedrops, available eyedrop assistive devices, and patient education regarding eyedrop instillation., Methods: PubMed, Embase, and Google Scholar were searched from conception until June 2022 for articles on eyedrop instillation difficulties, techniques, tools, and patient education., Results: Instillation involves pulling down the lower eyelids and placing drops on the corneal surface or conjunctival fornix, followed by closing of the eyelids for about 1 min. Examples of techniques include eyelid closure and nasolacrimal obstruction techniques. Patients encounter many difficulties when administering eyedrops, including but not limited to poor visibility, squeezing the dropper bottle, aiming the bottle, and accidentally blinking. However, devices are available that assist with aim and dropper compression-force reduction in eyedrop instillation. These can be particularly useful in patient demographics with diminished manual dexterity or the ability to generate force from their fingers. Furthermore, despite patient education in eyedrop instillation not being a common practice, it has been found that adequate patient education can lead to significant improvement in eyedrop instillation technique., Conclusions: While many factors are associated with poor eyedrop instillation technique, there are many solutions available including assistive devices and proper instillation education., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Current Ophthalmology.)

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses., Competing Interests: Declaration of interests B.Y.N., H.H., and D.S.S. are co-inventors on a provisional patent application filed by Genentech/Roche related to this manuscript. B.Y.N. is an employee and stockholder of Roche/Genentech. H.H. is an employee and stockholder of Roche/Genentech. R.B. is an employee and shareholder of Roche/Genentech. S.M. is an employee and shareholder of Roche. L.A. is an employee and shareholder of Roche. V.G. is an employee of Rancho Biosciences and a consultant to Roche/Genentech. M.C.L. is an employee of Roche/Genentech. A.M.E. is an employee of Roche/Genentech. M.K.S. is an employee and shareholder of Roche/Genentech. N.S.P. is an employee and shareholder of Roche/Genentech. K.A.S. is an employee of Roche/Genentech. R.J. is an employee and shareholder of Roche/Genentech. C.C. is an employee and shareholder of Roche/Genentech. P.S.C. is an employee and shareholder of Roche/Genentech. M.F. is an employee of Roche/Genentech. S.R. is an employee and shareholder of Roche/Genentech. L.M.M. is an employee and shareholder of Roche/Genentech. H.K. is an employee and shareholder of Roche/Genentech. J.D.M. receives royalties from the NIH and UTSW for distribution of human tumor cell lines and has the following grants: CA070907, CA213274, and CA213338. C.M.G. reports consulting/advisory fees from AstraZeneca, Bristol Myers Squibb, Catalyst Pharmaceuticals, Daiichi Sankyo, G1 Therapeutics, Insights Driven Research, Jazz Pharmaceuticals, and Monte Rosa Therapeutics, as well as speaking/travel fees from Aptitude Health, BeiGene, DAVA Oncology, MJH, and OncLive, and royalties from UpToDate, Inc. J.M.C. has been paid as a consultant for Sonata Therapeutics and also owns stock in Mirati Therapeutics. J.V.H. has advisory or consulting relationships with Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAtla, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, Blueprint Medicine, and Chugai Pharmaceuticals. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. L.A.B. has consulted regarding oncology drug development Merck Sharp & Dohme Corp., Arrowhead Pharmaceuticals, Chugai Pharmaceutical Co., AstraZeneca Pharmaceuticals, Genetech Inc., BeiGene, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, and Daiichi Sankyo. S.V.L. served as a paid consultant/advisor for oncology drug development with AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer-Ingelheim, Bristol-Myers Squibb, Catalyst, AstraZeneca, D2G, Daiichi Sankyo, Eisai, Elevation Oncology Epizyme, Genentech/Roche, Gilead, Guardant Health, Janssen, Ipsen, Jazz Pharmaceuticals, Kowa, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, Turning Point, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics and has received research funding (to institution). M.R. has received honoraria for lectures and consultancy from Amgen, AstraZeneca, BMS, BeiGene, Boehringer-Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. He has received compensation for membership of DMSB by Daiichi Sankyo and Sanofi. D.S.S. is an employee and stockholder of Roche/Genentech., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone 1 . However, there remains little consensus on the mechanism(s) of response with this combination 2 . Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8 + T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months., Methods: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments., Results: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I 2  = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I 2  = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision., Conclusion: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events., Prospero Registration: CRD42022314418., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses., Methods: Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety., Results: Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; P = .3504; median, 5.4 months tiragolumab v 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; P = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively., Conclusion: Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.

Background: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments., Objective: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients., Methods: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation). Patients were stratified into high- and low-risk groups (overall survival [OS] and progression-free survival [PFS] outcomes) based on serum tumor biomarker levels., Results: The CYFRA 21-1 and CA 125 biomarker combination predicted OS and PFS in patients with SD. Risk of death was ~4-fold higher for the biomarker-stratified high-risk versus low-risk SD patients (hazard ratio [HR] 3.80; 95% confidence interval [CI] 3.02-4.78; p < 0.0001). OS in patients with the low- and high-risk SD was comparable to that in patients with the CT-defined partial response (PR; HR 1.10; 95% CI 0.898-1.34) and progressive disease (PD) (HR 1.05; 95% CI 0.621-1.77), respectively. The findings were similar with PFS, and consistent across treatment arms., Conclusions: Biomarker testing shows potential for providing prognostic information to help direct treatment in NSCLC patients with SD. Prospective clinical studies are warranted.ClinicalTrials.gov: NCT02366143.

Although there have been numerous innovations in the management of retinal detachment (RD) over the past decades, there is still limited understanding of the pathophysiological processes that take place before and after repair. Summarizing key concepts using animal studies may allow for a better assessment of common pre- and postoperative microstructural abnormalities in RD. We performed a systematic literature review on Ovid MEDLINE, EMBASE, and Cochrane Controlled Register of Trials from January 1968 to January 2022, searching animal or human studies reporting retinal histologic changes following primary or induced RD. Thirty-two studies were included. Main cellular events were summarized: photoceptor apoptosis occurs as early as 12 hours after RD and, although most cells survive, there is extensive remodeling. Outer segments progressively degenerate, while inner segments are reorganized. Rod and cone opsins are redistributed, and rod axons retract while cones undergo changes in shape. Second- and third-order neurons rearrange their dendritic processes, and Müller cells become hypertrophic, growing into the subretinal space. Finally, retinal pigment epithelium cells undergo a change in their morphology. Acknowledging critical morphologic changes following RD is crucial in understanding why anatomical and functional outcomes can vary. Insights from histological studies, together with high-resolution imaging, may be key in identifying novel biomarkers in RD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To determine sociodemographic predictors of poor vision in children and adolescents less than 18 years of age in a large, nationally representative sample of the US population., Design: Retrospective, population-based cross-sectional study., Methods: Using data from the 2021 National Health Interview Survey (NHIS), participants less than 18 years of age for whom data were available on vision difficulty were included in our analysis. Our primary outcome was vision difficulty. Sociodemographic variables were investigated as predictors of vision difficulty. Logistic regression models were performed using Stata version 17.0. An odds ratio (OR) and 95% CI were reported for analyses., Results: The 2021 NHIS reported on 8261 children and adolescents, of whom 7373 had data pertaining to vision difficulty and were included in our sample. Vision difficulty was associated with being unable to afford medical care (OR = 2.60, 95% CI = 1.17, 5.80, P = 0.02) and having public health insurance (OR = 1.52, 95% CI = 1.09, 2.12, P = .01). Compared to children less than 5 years of age, children ranging from 5 to 8 years (OR = 4.29, 95% CI = 2.26, 8.15, P < .01) and adolescents ranging from 16 to 17 years (OR = 6.06, 95% CI = 3.17, 11.58, P < .01) had a higher odds of vision difficulty. Compared to participants for whom the highest level of education of adults in their family was grade 1 to 11, the odds of vision difficulty were lower in those whose parents had a professional school or doctoral degree (OR = 0.30, 95% CI = 0.11, 0.84, P = .02)., Conclusions: Multiple sociodemographic factors are associated with vision difficulty in young persons. In working toward achieving equity in vision health, it is imperative that disparities mediated by sociodemographic factors be addressed through public health policies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 &lt; 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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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 &lt; 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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Post-operative hyperamylasemia (POH) following pancreatoduodenectomy (PD) may play a key role in pathogenesis of post-operative pancreatic fistula (POPF). Aim of the current study was to evaluate efficacy of perioperative administration of indomethacin in preventing POH., Methods: Single-center, double-blind, randomized controlled trial (RCT) conducted on consecutive patients undergoing PD. Patients received either 100 mg of indomethacin per-rectally at induction of anesthesia or standard care. Primary endpoint was incidence of POH in the two arms. POH was defined as postoperative day (POD) 1 serum amylase (S. amylase) levels greater than the upper limit of normal., Results: After exclusion 44 patients were randomized. The two arms were comparable for preoperative and intraoperative parameters. POH was noted in 20/44 (45.5%) with significantly lower incidence of POH (60.9% vs. 28.6%, p = 0.032) in intervention arm (IA). Median S. amylase, POD 1, 3, and 5 drain amylase, and incidence of clinically relevant POPF (CR-POPF) were lower in IA but failed to reach statistical significance (30.4% vs. 14.3%, p = 0.18). The severity of delayed gastric emptying (DGE) was significantly lower in the IA (grade B/C DGE 23.8% vs. 47.8%, p = 0.023). Evaluation of risk factors for POH showed IA to confer an independent protective effect and increased risk with soft pancreas., Conclusion: Perioperative per-rectal indomethacin administration is effective in decreasing the incidence of POH following pancreatoduodenectomy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Upper gastrointestinal (GI) contrast studies are frequently requested to aid superior mesenteric artery syndrome diagnosis, a rare entity. Compression of the third duodenal part is expected to be mid-to-left of the midline where the superior mesenteric artery arises from the aorta; however, a duodenal impression to the right of the midline due to normal anatomic impression by the inferior vena cava (IVC) is often encountered and frequently misdiagnosed., Objective: The purpose of this study was to determine the frequencies of (1) normal right-of-midline duodenal impressions and (2) mid-to-left of midline compressions in upper GI studies in a tertiary pediatric referral center., Materials and Methods: All upper GI studies performed at our institution over 2 years were retrospectively evaluated to determine whether the duodenum had vertical duodenal impression to the right of the vertebral midline, mid-to-left of the vertebral midline, or no identifiable duodenal impression at all., Results: In total, 538 upper GI studies were included in this analysis. A total of 275 male and 247 female patients between 0 and 17 years of age (median: 6 years, range: 1 month-17 years) were included. Of 538 total upper GI studies, there were 240 studies (44.6%) with a right-of-midline impression. There were only 10 studies (1.9%) with a mid-to-left of midline compression, and 9/10 also showed a concurrent right-sided impression sign., Conclusion: Right-of-midline duodenal impression is a normal anatomic finding caused by the IVC and should not be confused with superior mesenteric artery syndrome. In the presence of an appropriate clinical context, proximal duodenal dilation, "to-and-fro" motion of contrast, and duodenal impression at mid-to-left of midline, a diagnosis of superior mesenteric artery syndrome should be considered., (© 2023. The Author(s).)

Objective: This study aimed at studying the challenges and outcomes of live-donor liver transplantation (LDLT) for pediatric acute liver failure (PALF)., Study Design: A total of 315 patients with PALF were treated over a period of 11 years. 42 underwent LT (41 LDLT and one DDLT), constituting 38% (41/110) of all pediatric transplants during this duration. The outcomes of LDLT for PALF were analyzed., Results: All the 41 children who underwent LT met the Kings College criteria (KCC). The etiology was indeterminate in 46.3% (n = 19) children. 75.6% (n = 31) were on mechanical ventilation for grade 3/4 hepatic encephalopathy. There was presence of cerebral edema on a computed tomography scan of the brain in 50% of the children. One-third of our children required hemodynamic support with vasopressors. Systemic inflammatory response syndrome and sepsis were observed in 46.3% and 41.4% of patients, respectively. Post-LDLT 1- and 5-yr patient and graft survival were 75.6% and 70.9%, respectively. The survival in children satisfying KCC but did not undergo LT was 24% (38/161). Vascular and biliary complication rates were 2.4% and 4.8%, respectively. No graft loss occurred because of acute rejection. In multivariate analysis, pre-LT culture positivity and cerebral edema, persistence of brain edema after transplantation, and resultant pulmonary complications were significantly associated with post-LT death. Thirteen (32%) children who underwent plasmapheresis prior to LT had better post-LT neurological recovery, as evidenced by early extubation., Conclusion: LDLT for PALF is lifesaving and provides a unique opportunity to time transplantation. Good long-term survival can be achieved, despite the majority of patients presenting late for transplantation. Early referral and better selection can save more lives through timely transplantation., (© 2023. Asian Pacific Association for the Study of the Liver.)

Importance: Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors., Objective: To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors., Design, Setting, and Participants: The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022., Interventions: Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity., Main Outcomes and Measures: The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables., Results: Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months)., Conclusions and Relevance: In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC., Trial Registration: ClinicalTrials.gov Identifier: NCT02794571.