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Benedicte Lescrauwaet,1 Koenraad Blot,2 Timothy L Jackson3 1Xintera, Outcomes Research, Ghent, Belgium; 2Xintera, Ghent, Belgium; 3Life Sciences and Medicine, King’s College London, Department of Ophthalmology, King’s College Hospital, London, UK Purpose: Vitreomacular traction (VMT) is a disease in which the vitreous exerts abnormally strong traction on the macula, the area of the eye responsible for detailed central vision. If this traction significantly distorts the macula then VMT can lead to troublesome distorted vision (metamorphopsia), sometimes occurring despite relatively preserved visual acuity. Ocriplasmin, administered as a single intravitreal injection, aims to release VMT and improve vision. While the effect of ocriplasmin on traction release and visual acuity is well characterized, the effect of symptoms like metamorphopsia is not.Methods: A systematic review and synthesis of the literature on patient reported outcomes (PRO) in relation to the use of ocriplasmin for the treatment of VMT was undertaken using MEDLINE and Embase databases, and the Cochrane central register of controlled trials (CENTRAL).Results: The review identified PRO data from 870 patients across three randomized controlled trials. The most commonly reported PROs were the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25), a broad measure of vision-related quality of life, and Visual Function Response (VFR), an outcome combining quality of life and visual acuity outcomes. Treatment with ocriplasmin produced significant patient benefit vs control (sham or placebo-injection). Ocriplasmin was associated with a higher proportion of patients experiencing a clinically meaningful improvement in visual functioning with a difference of 11.8% for VFQ-25 and 23.2% for VFR responder analyses, respectively.Conclusion: Patients with VMT have material impairment in visual functioning and quality of life, relative to their reduction in visual acuity. Ocriplasmin results in a significant improvement in visual functioning. Future research could include the development of new PROs specific to VMT. Keywords: macular hole, metamorphopsia, patient reported outcomes, symptomatic vitreomacular adhesion, vitreomacular traction, visual function questionnaire

Jacob Menzler,1 Aljoscha Steffen Neubauer,1,2 Christos Haritoglou,3 Timothy L Jackson4 1Institute for Health- and Pharmacoeconomics/Neubauer Consult, Munich, Germany; 2Private practice, Munich, Germany; 3Herzog Carl Theodor Eye Hospital, Munich, Germany; 4Department of Ophthalmology, Faculty of Life Course Sciences and Medicine, King’s College London, London, UK Purpose: Symptomatic vitreomacular adhesion (sVMA) comprises vitreomacular traction (VMT) and stage 1 and 2 full-thickness macular holes (MHs) associated with vitreomacular adhesion (VMA). We aimed to estimate the incidence and prevalence of sVMA in Germany.Materials and methods: A systematic literature review was conducted to identify the incidence and prevalence of sVMA based on international epidemiologic studies, weighted for study size and then averaged across eligible studies. A second systematic review aimed to estimate the proportion of vitrectomy undertaken for sVMA in Germany. This was combined with the reported number of vitrectomies in Germany in 2016 to estimate the number of patients undergoing vitrectomy for sVMA.Results: The prevalence of sVMA is 1,365 per 100,000 population, with an incidence of 6.96 per 100,000 per year. For Germany, this translates to 1,119,300 cases, with 5,700 new cases reported annually. Analyzing the national hospital statistics, ~2,300 patients undergo vitrectomy due to sVMA in Germany each year, of which about 1,700 patients have VMT.Conclusion: Incidence figures, driven by patients presenting to clinic, are much lower than expected based on population-based studies, suggesting that many patients with sVMA exist outside of the clinic system. Keywords: epidemiology, vitreous body, vitreous pathology, vitreous adhesion, vitreous detachment, pars plana vitrectomy

James E Neffendorf, Timothy L Jackson Department of Ophthalmology, School of Medicine, King’s College London, London, United Kingdom Abstract: Neovascular age-related macular degeneration is a leading cause of blindness in the developed world. Currently, the treatment of choice is intravitreal injections of anti-VEGF medications. These require frequent dosing, up to monthly, and impose a substantial burden on patients and the health economy. Ionizing radiation was proposed as a possible treatment for age-related macular degeneration due to its anti-inflammatory and anti-fibrotic properties. Stereotactic radiotherapy is an outpatient-based radiotherapy platform that provides stereotactic application of low energy X-ray to the retina in three highly collimated beams that cross the inferior sclera to overlap at the macula. A randomized, double-masked, sham-controlled trial of 230 patients (INTREPID) showed that a single dose of stereotactic radiotherapy significantly reduces the number of intravitreal anti-VEGF injections needed over 2 years. A larger randomized controlled trial (STAR) is underway. Keywords: wet age-related macular degeneration, radiation therapy, stereotactic radiotherapy, vascular endothelial growth factor

We present a mathematical model that describes thermo-mechanical deformations and thermal gradients on the unsteady burning of a heterogeneous solid propellant. A scaling study shows that the deformations in solid at combustion timescales can be treated as quasi-static. The resulting thermo-mechanical formulation is formulated on a Cartesian grid and makes use of a weak form of Chorin-type projection method to deal with large difference in shear modulus of constituent materials. A one-dimensional verification study is carried out by comparing numerical simulations with those of an analytical model. In addition, convergence studies for a two-dimensional propellant sandwich configuration are presented for the stress, velocity, and reference map components. Finally, simulations are carried out for a two-dimensional random propellant pack and the time-averaged burn rate and strains are reported.

As coastal urbanization increases globally, the subsequent effects on marine animals, especially endangered species, inhabiting nearshore waters have become a research priority. The smalltooth sawfish Pristis pectinata, once abundant in US waters, now only persists in a few parts of its former range, including South Florida. Many areas utilized by smalltooth sawfish are estuarine systems or other shallow coastal habitats, making this species particularly vulnerable to threats associated with coastal development. To date, P. pectinata has been understudied in the waters in and around Biscayne Bay, Florida, a coastal waterway subjected to the urbanization of adjacent Miami-Dade County. Here, we summarize data from reported smalltooth sawfish encounters dating as far back as 1895 (N = 90) and detail opportune recordings (incidental catches, acoustic detections, and baited remote underwater videos) of sub-adults and adults (N = 14 individuals) in Biscayne Bay and the adjacent reef tract. These data demonstrate historical and increased contemporary use of the study area by this imperiled species, suggesting potential local and regional recovery. Most documented sawfish occurrences were near the urban center, indicating a need to understand the effects of coastal urbanization on sawfish and on the species' recovery potential. We suggest priorities for future research on P. pectinata in the study area that will assist in addressing regional management goals and contribute to understanding the ecology of smalltooth sawfish under environmental change.

N2 is a diatomic molecule with complex electronic structure. Interstate crossings are prominent in the high energy domain, introducing significant perturbations to the system. Nitrogen mainly photodissociates in the vacuum ultraviolet (VUV) region of the electromagnetic spectrum through both direct and indirect predissociation. Due to the complexity introduced by these perturbations, the nitrogen isotopic fractionation in N2 photodissociation is extremely hard to calculate, and an experimental approach is required. Here we present new data of N-isotopic fractionation in N2 photodissociation at low temperature (80 K), which shows a distinctly different 15N enrichment profile compared to that at relatively higher temperatures (200 and 300 K). The new data, important to understanding the N-isotopic compositions measured in meteorites and other planetary bodies, are discussed in light of the knowledge of N2 photochemistry and calculated photoabsorption cross sections in the VUV.

The 17O excess (Δ170= δΔ17O-0.52×δ18O) of sulfate and nitrate reflects the relative importance of their different production pathways in the atmosphere. A new record of sulfate and nitrate Δ17O spanning the last 2400 years from the West Antarctic Ice Sheet Divide ice core project shows significant changes in both sulfate and nitrate Δ17O in the most recent 200 years, indicating changes in their formation pathways. The sulfate Δ17O record exhibits a 1.1% increase in the early 19th century from (2.4 ± 0.2)% to (3.5 ± 0.2)%, which suggests that an additional 12-18% of sulfate formation occurs via aqueous-phase production by O3, relative to that in the gas phase. Nitrate Δ17O gradually decreases over the whole record, with a more rapid decrease between the mid-19th century and the present day of 5.6%, indicating an increasing importance of RO2 in NOx cycling between the mid-19th century and the present day in the mid- to high-latitude Southern Hemisphere. The former has implications for the climate impacts of sulfate aerosol, while the latter has implications for the tropospheric O 3 production rate in remote low-NOx environments. Using other ice core observations, we rule out drivers for these changes other than variability in extratropical oxidant (OH, O3, RO2, H 2O2, and reactive halogens) concentrations. However, assuming OH, H2O2, and O3 are the main oxidants contributing to sulfate formation, Monte Carlo box model simulations require a large (≥260%) increase in the O3/OH mole fraction ratio over the Southern Ocean in the early 19th century to match the sulfate Δ17O record. This unlikely scenario points to a deficiency in our understanding of sulfur chemistry and suggests other oxidants may play an important role in sulfate formation in the mid- to high-latitude marine boundary layer. The observed decrease in nitrate Δ17O since the mid-19th century is most likely due to an increased importance of RO2 over O3 in NOx cycling and can be explained by a 60-90% decrease in the O 3/RO2 mole fraction ratio in the extratropical Southern Hemisphere NOx-source regions. © Author(s) 2014.

Objective: We examined the usability of common formats of pictorial toy assembly instructions for 6- and 9-year-old children.Background: Interlocking building toys and models are increasingly prevalent and important for developing spatial abilities and fine motor skills among children. Little is known about how effectively the intended child users can interpret and carry out the instructions.Method: Twenty-four children used five sets of manufacturer-supplied pictorial toy assembly instructions. We evaluated the impact of toy instruction set, age, gender, and previous experience on usability problems, assembly speed and accuracy, instruction gaze time, and subjective ratings.Results: The children had difficulty with all but the simplest instructions and assemblies. As predicted, older participants assembled more quickly, with fewer errors and fewer instruction looks. However, the 6-year-old girls assembled the fewest parts correctly, and the 9-year-old girls reported having the least fun. Instruction look time and frequency revealed differences in instruction complexity and were correlated with subjective ratings of fun. Thirty-two usability problems were observed, and 10 are described in detail.Conclusion: Product age recommendations may not reflect developmentally appropriate instructions. Small design changes should contribute to improved instruction usability among young children. For instance, designers should avoid complex graphic syntax, depict colors accurately, select clear angles of view, and support natural tendencies to assemble top to bottom.Application: This research provides pictorial assembly instruction guidelines to inform instruction designers and describes performance and look-time benchmarks for future usability studies. [ABSTRACT FROM AUTHOR]

In the U.S.A., Material Safety Data Sheets (MSDSs) are required by the Occupational Safety and Health Administration (OSHA). Mental model theories of cognitive processing predict that information format inconsistencies can undermine usability and thereby worker safety and compliance. The present study explored whether information presentation priorities are dependent upon the population tested. Ninety participants were sampled from three populations (undergraduates, community volunteers, and firefighters). Participants sorted cards containing chunks of information comprised of MSDS headings and text. Mean rank analyses showed that health-related information was given higher priority than other information, such as reactivity or chemical make-up. While there were similarities for the different subgroups, the firefighters differed from the other two groups in several respects. Results were consistent with previous research on schema differences between groups based upon experience and expectations. Implications for MSDS design and application of usability and mental model approaches to improve safety communications are discussed. [ABSTRACT FROM AUTHOR]

Importance: Evidence is limited to support therapies to treat submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) as an adjunct to anti-vascular endothelial growth factor therapy (anti-VEGF)., Objective: To determine if intravitreal tissue plasminogen activator (TPA) or gas improves visual acuity or promotes resolution of SMH secondary to neovascular AMD in eyes treated with ranibizumab., Design, Setting, and Participants: This was a double-masked, sham-controlled, factorial randomized clinical trial and feasibility study that recruited participants from June 2014 to March 2019, with 12 months' follow-up. Included in the trial were patients from 4 UK vitreoretinal units who had fovea-involving SMH of at least 1 disc area secondary to neovascular AMD and were evaluated within 14 days of onset., Interventions: Study eyes received baseline ranibizumab and were then randomized 2:1:1:1 to 1 of 4 intravitreal treatments: sham injection, perfluoropropane (C3F8), TPA, or combined C3F8 and TPA (C3F8 + TPA). All eyes received monthly pro re nata ranibizumab therapy over 12 months. Outcome assessors were masked to intervention assignment., Main Outcome and Measure: Best-corrected visual acuity (BCVA) at month 3., Results: Fifty-three of 56 participants (95%; mean [SD] age, 81.5 [8.1] years; 33 female [59%]) reached the primary end point. Study eyes were randomized to the following intravitreal treatments: sham injection (n = 23), C3F8 (n = 11), TPA (n = 11), or C3F8 + TPA (n = 11). On factorial analysis, the combined TPA groups had significantly better month 3 mean logMAR BCVA than those not receiving TPA: 0.66 vs 0.98 (μd = -0.32; 95% CI, -0.58 to -0.07; P = .02). There was no statistically significant difference comparing groups that did vs did not receive C3F8: 0.80 vs 0.90 (μd = -0.11; 95% CI, -0.37 to 0.16; P = .43). The combined TPA groups were less likely to have SMH present at month 1 (10 of 18 [55.6%] vs 21 of 24 [87.5%]; P = .03), a benefit not evident in the combined gas groups. The mean logMAR BCVA at 3 months was not significantly different between the groups: monotherapy control, 0.99; C3F8, 0.97 (vs control μd = -0.02; 95% CI, -0.48 to 0.44); TPA, 0.70 (vs control μd = -0.29; 95% CI, -0.79 to 0.21); combined C3F8 and TPA, 0.71 (vs control μd = -0.36; 95% CI, -0.82 to 0.11); P = .11. No safety differences were identified across the treatment groups., Conclusions and Relevance: Results of this randomized clinical trial suggest that TPA may increase the chance of visual acuity gain when added to ranibizumab therapy for neovascular AMD in eyes with SMH, warranting consideration of additional clinical trials., Trial Registration: ClinicalTrials.gov Identifier: NCT01835067.

Modern mediation analysis techniques supplement the primary intention-to-treat analysis with the aim to shed light onto the treatment mechanism. We investigate to what extent the anatomic marker vitreomacular adhesion resolution (VMAR) mediates vision benefits, comparing ocriplasmin vs. a sham regimen. A causal mediation analysis is applied to randomized trial data including 218 participants with vitreomacular traction. Logistic regression models are used to estimate the total treatment effect (TTE) on binary outcomes. Outcomes, assessed at month 24, included visual acuity improvement (VA-I): ≥2-line increase in VA; visual function questionnaire improvement (VFQ-I): ≥5-point increase in the 25-item visual function questionnaire composite score (VFQ-25cs); visual function improvement (VF-I): defined as either a VA-I or a clinically meaningful improvement in the VFQ-25cs. Quantity of interest is the breakdown of TTE into an indirect (through VMAR) and direct effect to estimate the extent to which the TTE is transmitted through the mediating variable (VMAR) vs. other pathways. Causal effects are expressed as risk differences. Indirect effects for VFQ-I, VA-I, and VF-I are 5.7%, 11.8%, and 5.2%, respectively, representing the increase in the probability of a vision improvement if VMAR status were changed for each participant to the extent that it is affected by ocriplasmin. The direct effects are 8.3%, 12.1%, and 24.1% respectively, capturing the effect of treatment on the probability of a vision improvement if ocriplasmin left each participant's VMAR status unchanged. The relative treatment effect of ocriplasmin on the functional outcome VA-I is to a large extent the result of its effect on VMAR, while an improvement in the patient-reported outcomes VFQ-I or VF-I was only partially mediated by VMAR., Competing Interests: Conflicts of InterestThe authors declare the following conflicts of interest: BL reports the following: Consultant: Oxurion; Regenxbio. SV reports the following: Consultant: Janssen Pharmaceuticals; Novo Nordisk. Lecture Fees/Speakers Bureau: Janssen Pharmaceuticals; Grants/contracts: GSK. TLJ reports the following: Consultant: DORC, Alcon, iLumen, Opthea, Outlook Therapeutics, 2CTech; Expert testimony: Allan & Overy; Meetings and/or travel support: Roche: Equipment, drugs: LKC, Zeiss, Bayer. Research contracts: Oxurion; Misc commercial retinal trials. SVS reports the following: Consultant/Advisor: 4DMT, Alexion, Allergan, Inc., Alnylam Pharmaceuticals, Amgen Inc., Apellis Pharmaceuticals, Inc., Astellas, Bayer Healthcare Pharmaceuticals, Biogen, Boerhinger Ingelheim, Carl Zeiss Meditec, Catalyst Pharmaceuticals Inc, Centervue, Inc., GENENTECH; Gyroscope Therapeutics, Heidelberg Engineering, Iveric Bio, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Nanoscope, Novartis Pharma AG, Optos, Inc., Oxurion/ Thrombogenics, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Samsung Bioepis, Vertex Pharmaceuticals Inc.; Lecture Fees/Speakers Bureau: Carl Zeiss Meditec, Heidelberg Engineering, Nidek Inc., Novartis Pharma AG, Topcon Medical Systems Inc.; Grant Support: Carl Zeiss Meditec, Heidelberg Engineering. LD reports the following: Consultant: Oxurion. Oxurion provided the individual-participant-level data. The sponsor had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (© 2024 by the authors.)

As an adoptive cellular therapy, Chimeric Antigen Receptor T cell (CAR T cell) therapy has shown remarkable success in hematological malignancies but only limited efficacy against solid tumors. Compared with blood cancers, solid tumors present a series of challenges that ultimately combine to neutralize the function of CAR T cells. These challenges include, but are not limited to, antigen heterogeneity - variability in the expression of the antigen on tumor cells, as well as trafficking and infiltration into the solid tumor tissue. A critical question for solving the heterogeneity problem is whether CAR T therapy induces bystander effects, such as antigen spreading. Antigen spreading occurs when CAR T cells activate other endogenous antitumor CD8 T cells against antigens that were not originally targeted. In this work, we develop a mathematical model of CAR T cell therapy for solid tumors that considers both antigen heterogeneity and bystander effects. Our model is based on in vivo treatment data that includes a mixture of target antigen-positive and target antigen-negative tumor cells. We use our model to simulate large cohorts of virtual patients to better understand the relationship involving bystander killing. We also investigate several strategies for enhancing bystander effects, thus increasing CAR T cell therapy's overall efficacy for solid tumors., (© 2024. The Author(s).)

Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations.

Background: Predicting diabetic retinopathy (DR) progression could enable individualised screening with prompt referral for high-risk individuals for sight-saving treatment, whilst reducing screening burden for low-risk individuals. We developed and validated deep learning systems (DLS) that predict 1, 2 and 3 year emergent referable DR and maculopathy using risk factor characteristics (tabular DLS), colour fundal photographs (image DLS) or both (multimodal DLS)., Methods: From 162,339 development-set eyes from south-east London (UK) diabetic eye screening programme (DESP), 110,837 had eligible longitudinal data, with the remaining 51,502 used for pretraining. Internal and external (Birmingham DESP, UK) test datasets included 27,996, and 6928 eyes respectively., Results: Internal multimodal DLS emergent referable DR, maculopathy or either area-under-the receiver operating characteristic (AUROC) were 0.95 (95% CI: 0.92-0.98), 0.84 (0.82-0.86), 0.85 (0.83-0.87) for 1 year, 0.92 (0.87-0.96), 0.84 (0.82-0.87), 0.85 (0.82-0.87) for 2 years, and 0.85 (0.80-0.90), 0.79 (0.76-0.82), 0.79 (0.76-0.82) for 3 years. External multimodal DLS emergent referable DR, maculopathy or either AUROC were 0.93 (0.88-0.97), 0.85 (0.80-0.89), 0.85 (0.76-0.85) for 1 year, 0.93 (0.89-0.97), 0.79 (0.74-0.84), 0.80 (0.76-0.85) for 2 years, and 0.91 (0.84-0.98), 0.79 (0.74-0.83), 0.79 (0.74-0.84) for 3 years., Conclusions: Multimodal and image DLS performance is significantly better than tabular DLS at all intervals. DLS accurately predict 1, 2 and 3 year emergent referable DR and referable maculopathy using colour fundal photographs, with additional risk factor characteristics conferring improvements in prognostic performance. Proposed DLS are a step towards individualised risk-based screening, whereby AI-assistance allows high-risk individuals to be closely monitored while reducing screening burden for low-risk individuals., (© 2024. The Author(s).)

Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity., Methods: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment., Findings: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483)., Interpretation: SRT can reduce ranibizumab treatment burden without compromising vision., Funding: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme., Competing Interests: Declaration of interests Oraya/Zeiss provided free use of the SRT device at the STAR National Treatment Centres. BCR, TP, YW, HAW, JMO, and JP declare no competing interests. TLJ is a consultant or adviser to 2CTech, Alcon, Dutch Ophthalmic Research Centre, iLumen, Opthea, Outlook Therapeutics, Oxurion, and Regeneron. He has received conference support from Roche, and an advisory board payment from Oraya in 2013. TP has participated in advisory boards for Apellis and received investigator initiated research funds paid to her institution from Boehringen Ingelheim; as well as receiving speakers fees from Heidelberg, Zeiss, and Optos. UC serves on a data monitoring committee for Adverum and is a consultant to Apellis, Boehringer Ingelheim, Isarna, Iveric, and Hoffman La Roche. JEN is an adviser to Solvemed, has received lecture fees from Novartis, and has received conference support from Dutch Ophthalmic Research Centre. HD and SW are financially supported in part by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre. CNL has undertaken contracting work for Opthea. TLJ, LR, RD, CNL, CL, PC and JEN's NHS employer receives site fees for patients enrolled on commercial retinal trials of AMD and other conditions., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims/hypothesis: A protective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin., Methods: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan-Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA 1c , BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed., Results: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208)., Conclusions/interpretation: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated  retinal imaging are required to determine the causal relationship with these therapies., (© 2024. The Author(s).)

Background: The COVID-19 pandemic negatively affected adolescent mental health due to school closures, isolation, family loss/hardships, and reduced health care access., Methods: We compared adolescent mental health in Rhode Island before versus during the pandemic, separately among middle and high schoolers. This serial cross-sectional study used Youth Risk Behavior Survey data from 2019 and 2021 (N = 7403). Multivariable logistic regression models estimated the association between year and mental health status, adjusting for sociodemographics., Results: Middle schoolers in 2021 had higher odds of ever seriously considering suicide (22.6% vs 16.7%) and ever attempting suicide (9.3% vs 6.1%) compared to 2019. Among high schoolers, those in 2021 had higher odds of experiencing persistent sadness/hopelessness in the past year (37.4% vs 32.0%). However, high schoolers in 2019 and 2021 had similar odds of considering suicide in the past year, while those in 2021 had lower odds of having attempted suicide in the past year (8.5% vs 14.6%)., Conclusion: The COVID-19 pandemic may have worsened multiple aspects of adolescent mental health in Rhode Island, particularly among middle schoolers., Implications for School Health Policy, Practice, and Equity: Promoting school connectedness, creating supportive environments, and diversifying the mental health workforce may help overcome adverse pandemic effects., (© 2023, American School Health Association.)

Purpose: To determine associations between deprivation using the Index of Multiple Deprivation (IMD and individual IMD subdomains) with incident referable diabetic retinopathy/maculopathy (termed rDR)., Methods: Anonymised demographic and screening data collected by the South-East London Diabetic Eye Screening Programme were extracted from September 2013 to December 2019. Multivariable Cox proportional models were used to explore the association between the IMD, IMD subdomains and rDR., Results: From 118 508 people with diabetes who attended during the study period, 88 910 (75%) were eligible. The mean (± SD) age was 59.6 (±14.7) years; 53.94% were male, 52.58% identified as white, 94.28% had type 2 diabetes and the average duration of diabetes was 5.81 (±6.9) years; rDR occurred in 7113 patients (8.00%). Known risk factors of younger age, Black ethnicity, type 2 diabetes, more severe baseline DR and diabetes duration conferred a higher risk of incident rDR. After adjusting for these known risk factors, the multivariable analysis did not show a significant association between IMD (decile 1 vs decile 10) and rDR (HR: 1.08, 95% CI: 0.87 to 1.34, p=0.511). However, high deprivation (decile 1) in three IMD subdomains was associated with rDR, namely living environment (HR: 1.64, 95% CI: 1.12 to 2.41, p=0.011), education skills (HR: 1.64, 95% CI: 1.12 to 2.41, p=0.011) and income (HR: 1.19, 95% CI: 1.02 to 1.38, p=0.024)., Conclusion: IMD subdomains allow for the detection of associations between aspects of deprivation and rDR, which may be missed when using the aggregate IMD. The generalisation of these findings outside the UK population requires corroboration internationally., Competing Interests: Competing interests: PG, PN, JMNdR, LW, SM, DH, MJC, MM and CB has no conflicts of interest to declare. TLJ’ employer (King’s College Hospital) receives funding for participants enrolled on commercial clinical trials of diabetic retinopathy including THR149-002 (sponsor: OXURION), NEON NPDR (sponsor: BAYER), RHONE-X (sponsor: ROCHE) and ALTIMETER (sponsor: ROCHE). He is a paid advisor to solicitors acting for REGENERON and has received conference support from ROCHE., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy is commonly used intravitreally for diabetic proliferative retinopathy, but when used systemically for treating cancers, an excess of cardiovascular disease (CVD) events has been noted. The latter is of concern for people with diabetes, who are at higher risk of CVD. This study aims to explore the relationship between incident CVD and intravitreal anti-VEGF therapy in patients with diabetes, compared to other therapies, using a large real-world global federated dataset., Methods: Data were analysed using TriNetX, a global electronic medical real-world ecosystem. The study included adults with diabetes and excluded those with a history of CVD prior to the time window of data extraction. Patients were categorised into two cohorts: anti-VEGF therapy or control cohort (laser or steroid therapies). The cohorts were 1:1 propensity score-matched for age, sex, ethnicity, body mass index, systolic blood pressure, HbA1c, and cardiovascular medications. Outcomes analysed at 1, 6 and 12 months were: (1) mortality; (2) acute myocardial infarction (MI); (3) cerebral infarction; and (4) heart failure. Relative risk analyses were performed using the built-in R statistical computing platform on TriNetX., Results: In patients with diabetes (n = 2205; mean age 58.8 ± 15.8, Std diff 0.05; 56% male), anti-VEGF therapy was associated with a numerical but non-statistically significant increased CVD risk over 1, 6, and 12 months: Mortality over 1 month (RR 1; 95% CI 0.42, 2.40), 6 months (RR 1.46; 95% CI 0.72, 2.95) and 12 months (RR 1.41; 95% CI 0.88, 2.27). There was no excess of acute MI over 1 (RR n/a: not applicable; 0/0: 0 events in the anti-VEGF group/0 events in the control group), 6 and 12 months (RR n/a; 0/10 events); cerebral infarction over 1, 6 months (RR n/a; 0/0 events), and 12 months (RR n/a; 0/10); and heart failure over 1 month (RR n/a; 0/0 events), 6 months (RR 1; 95% CI 0.42, 2.40) and 12 months (RR 1; 95% CI 0.42, 2.34)., Conclusions: There was no statistically significant risk of cardiovascular-related events in the short or medium term in patients with diabetes who received intravitreal anti-VEGF therapy, despite a small increase in the number of CVD events. Our study supports the real-world safety of intravitreal anti-VEGF therapy in patients with diabetes free of baseline CVD., (© 2024. The Author(s).)

Bladder cancer is an increasingly prevalent global disease that continues to cause morbidity and mortality despite recent advances in treatment. Immune checkpoint inhibitors (ICI) and fibroblast growth factor receptor (FGFR)-targeted therapeutics have had modest success in bladder cancer when used as monotherapy. Emerging data suggests that the combination of these two therapies could lead to improved clinical outcomes, but the optimal strategy for combining these agents remains uncertain. Mathematical models, specifically agent-based models (ABMs), have shown recent successes in uncovering the multiscale dynamics that shape the trajectory of cancer. They have enabled the optimization of treatment methods and the identification of novel therapeutic strategies. To assess the combined effects of anti-PD-1 and anti-FGFR3 small molecule inhibitors (SMI) on tumor growth and the immune response, we built an ABM that captures key facets of tumor heterogeneity and CD8 + T cell phenotypes, their spatial interactions, and their response to therapeutic pressures. Our model quantifies how tumor antigenicity and FGFR3 activating mutations impact disease trajectory and response to anti-PD-1 antibodies and anti-FGFR3 SMI. We find that even a small population of weakly antigenic tumor cells bearing an FGFR3 mutation can render the tumor resistant to combination therapy. However, highly antigenic tumors can overcome therapeutic resistance mediated by FGFR3 mutation. The optimal therapy depends on the strength of the FGFR3 signaling pathway. Under certain conditions, ICI alone is optimal; in others, ICI followed by anti-FGFR3 therapy is best. These results indicate the need to quantify FGFR3 signaling and the fitness advantage conferred on bladder cancer cells harboring this mutation. This ABM approach may enable rationally designed treatment plans to improve clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bergman, Wang, Trujillo, Fernald, Li, Pearson, Sweis and Jackson.)

Background: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC)., Methods: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts., Results: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1 C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001)., Interpretation: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM., (© 2024 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Immunotherapy has dramatically transformed the cancer treatment landscape largely due to the efficacy of immune checkpoint inhibitors (ICIs). Although ICIs have shown promising results for many patients, the low response rates in many cancers highlight the ongoing challenges in cancer treatment. Cytotoxic T lymphocytes (CTLs) execute their cell-killing function via two distinct mechanisms: a fast-acting, perforin-mediated process and a slower, Fas ligand (FasL)-driven pathway. Evidence also suggests that the preferred killing mechanism of CTLs depends on the antigenicity of tumor cells. To determine the critical factors affecting responses to ICIs, we construct an ordinary differential equation model describing in vivo tumor-immune dynamics in the presence of active or blocked PD-1/PD-L1 immune checkpoint. Specifically, we identify important aspects of the tumor-immune landscape that affect tumor size and composition in the short and long term. We also generate a virtual cohort of mice with diverse tumor and immune attributes to simulate the outcomes of immune checkpoint blockade in a heterogeneous population. By identifying key tumor and immune characteristics associated with tumor elimination, dormancy, and escape, we predict which fraction of a population potentially responds well to ICIs and ways to enhance therapeutic outcomes with combination therapy., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Postpartum hemorrhage , defined as a cumulative blood loss of 1,000 mL or more or blood loss associated with signs or symptoms of hypovolemia regardless of the route of delivery, is the leading cause of preventable maternal death worldwide. The United States has one of the highest maternal mortality rates among developed countries, with about 14% of all maternal deaths associated with postpartum hemorrhage. Although postpartum hemorrhage has multiple causes, the most common is uterine atony-when the uterus fails to adequately contract after childbirth-accounting for 80% of all postpartum hemorrhages. When postpartum hemorrhage occurs despite preventive measures, therapeutic measures are used. Intrauterine hemorrhage-control devices are often the second-line therapy when medical management is unsuccessful. Despite its widespread use in current obstetric practice, the mechanism of intrauterine balloon tamponade, such as the Bakri balloon, is counterintuitive to the physiologic uterine contraction that occurs after delivery to control bleeding, and data on its effectiveness are mixed. Vacuum-induced hemorrhage control, such as with the Jada System, cleared by the U.S. Food and Drug Administration in 2020, is a novel modality for control of postpartum bleeding. It mimics postpartum physiology by applying low-level intrauterine negative pressure to facilitate uterine compressive forces, thereby constricting blood vessels to achieve hemostasis. Preliminary data from four studies are promising but are limited by a lack of control groups, selection bias, or modest sample sizes. The results of ongoing and planned randomized controlled trials will clarify the role of the Jada System for reducing morbidity from postpartum hemorrhage., Competing Interests: Financial Disclosure Methodius G. Tuuli reports that money was paid to his prior institution from Alydia Inc for research. Tracy L. Jackson did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background/aim: To assess the long-term safety and efficacy of epimacular brachytherapy (EMB) for chronic, active, neovascular age-related macular degeneration (nAMD)., Methods: This pivotal, randomised, controlled surgical device trial recruited patients with chronic nAMD receiving intravitreal ranibizumab from 24 UK hospitals. Participants were randomised to either pars plana vitrectomy with 24 Gray EMB and pro re nata (PRN) ranibizumab (n=224) or PRN ranibizumab monotherapy (n=119). Although masking was not possible, masked clinicians assessed best-corrected visual acuity (BCVA) and imaging. After month 24, participants reverted to standard care, with either ranibizumab or aflibercept, returning for a month 36 study visit., Results: Of 363 participants, 309 (85.1%) completed month 36. The number of injections was 12.1±8.1 in the EMB group versus 11.4±6.1 in the ranibizumab group (difference 0.7, 95% CI of difference -0.9 to 2.3, p = 0.41) between months 1 and 36, and 3.6±3.3 (n=200) versus 3.9±2.7 (n=102) (difference -0.3, 95% CI of difference -1.0 to 0.4, p=0.43) between months 25 and 36 (standard care). Over 36 months, BCVA change was -19.7±18.5 letters in the EMB group and -4.8±12.5 in the ranibizumab group (difference -14.9, 95% CI of difference -18.5 to -11.2, p < 0.0001). The month 36 BCVA of 20 EMB-treated participants with microvascular abnormalities (MVAs) at month 24 was similar to EMB-treated participants without MVAs (-21.8 vs -19.4 letters, p = 0.65)., Conclusion: EMB does not reduce the number of anti-vascular endothelial growth factor (VEGF) injections, either within or outside of a trial setting, and is associated with worse BCVA than anti-VEGF monotherapy., Trial Registration Number: NCT01006538., Competing Interests: Competing interests: TLJ received conference support and his employer received unrestricted research grant support from NeoVista. NeoVista had no role in data collection, analysis, or in the preparation or review of this manuscript. TLJ’s employer received free use of equipment from Oraya for an investigator-initiated trial of SRT, and his employer received research funding from Novartis for an unrelated project. His employer receives site payments for participants enrolled in various commercial clinical trials of AMD., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Neovascular (wet) age-related macular degeneration (nAMD) is driven by VEGFs A, C, and D, which promote angiogenesis and vascular permeability. Intravitreal injections of anti-VEGF-A drugs are the standard of care, but these do not inhibit VEGF-C and D, which may explain why many patients fail to respond fully. This trial aimed to test the safety and efficacy of OPT-302, a biologic inhibitor of VEGF-C and D, in combination with the anti-VEGF-A inhibitor ranibizumab., Design: Dose-ranging, phase 2b, randomized, double-masked, sham-controlled trial., Participants: Participants with treatment-naive nAMD were enrolled from 109 sites across Europe, Israel, and the United States., Methods: Participants were randomized to 6, 4-weekly, intravitreal injections of 0.5 mg OPT-302, 2.0 mg OPT-302, or sham, plus intravitreal 0.5 mg ranibizumab., Main Outcome Measures: The primary outcome was mean change in ETDRS best-corrected visual acuity (BCVA) at 24 weeks. Secondary outcomes (comparing baseline with week 24) were the proportion of participants gaining or losing ≥ 15 ETDRS BCVA letters; area under the ETDRS BCVA over time curve; change in spectral-domain OCT (SD-OCT) central subfield thickness; and change in intraretinal fluid and subretinal fluid on SD-OCT., Results: Of 366 participants recruited from December 1, 2017, to November 30, 2018, 122, 123, and 121 were randomized to 0.5 mg OPT-302, 2.0 mg OPT-302, and sham, respectively. Mean (± standard deviation) visual acuity gain in the 2.0 mg OPT-302 group was significantly superior to sham (+14.2 ± 11.61 vs. +10.8 ± 11.52 letters; P = 0.01). The 0.5 mg OPT-302 group was not significantly different than the sham group (+9.44 ± 11.32 letters; P = 0.83). Compared with sham, the secondary BCVA outcomes favored the 2.0 mg OPT-302 group, with structural outcomes favoring both OPT-302 dosage groups. Adverse events (AEs) were similar across groups, with 16 (13.3%), 7 (5.6%), and 10 (8.3%) participants in the lower-dose, higher-dose, and sham groups, respectively, developing at least 1 serious AE. Two unrelated deaths both occurred in the sham arm., Conclusions: Significantly superior vision gain was observed with OPT-302 2.0 mg combination therapy, versus standard of care, with favorable safety (ClinicalTrials.gov identifier: NCT03345082)., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. All rights reserved.)

Purpose: The purpose is to assess the effect of ethnicity on surgical macular hole closure., Methods: A retrospective cohort study was undertaken in five UK National Health Service Hospitals. We included all patients with known ethnicity undergoing vitrectomy, internal limiting membrane peel, and gas/oil tamponade for all stages of primary full-thickness macular hole (FTMH). The primary outcome was anatomic success, defined as FTMH closure with one operation. The secondary outcome was mean change in best-corrected visual acuity (BCVA) comparing baseline with final review., Results: Of 334 operations, the ethnicity profile comprised 78.7% White patients, 11.7% Black patients, 8.1% Asian patients, and 1.5% in mixed/other ethnicities. Mean age was 69.7 years with 68.5% females. Overall, 280 (83.8%) had anatomic success. Anatomic failure occurred in 38.5% of Black patients versus 12.6% of White patients (relative risk: 1.788; 95% CI: 1.012 to 3.159; P = 0.045). Overall, baseline logarithm of the minimum angle of resolution BCVA improved by 0.34, from 0.95 (95% CI: 0.894 to 1.008) to 0.62 (95% CI: 0.556 to 0.676). Mean BCVA improved by 0.35 in White patients, 0.37 in Black patients, 0.23 in Asian patients, and 0.38 in mixed/other ethnicity (P = 0.689). Greater FTMH minimum linear diameter was associated with an increased risk of anatomic failure (relative risk: 1.004; 95% CI: 1.002 to 1.005; P < 0.0001), whereas better pre-operative BCVA (F [1,19] = 162.90; P < 0.0001) and anatomic success (F [1,19] = 97.69; P < 0.0001) were associated with greater BCVA improvement. Socio-economic status did not significantly influence anatomic success or BCVA change., Conclusions: Black ethnicity is associated with an approximately twofold greater risk of failed FTMH surgery. The reasons for this difference warrant further study., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent years have seen the emergence and application of artificial intelligence (AI) in diagnostic decision support systems. There are approximately 80 etiologies that can underly uveitis, some very rare, and AI may lend itself to their detection. This synthesis of the literature selected articles that focused on the use of AI in determining the diagnosis, classification, and underlying etiology of uveitis. The AI-based systems demonstrated relatively good performance, with a classification accuracy of 93-99% and a sensitivity of at least 80% for identifying the two most probable etiologies underlying uveitis. However, there were limitations to the evidence. Firstly, most data were collected retrospectively with missing data. Secondly, ophthalmic, demographic, clinical, and ancillary tests were not reliably integrated into the algorithms' dataset. Thirdly, patient numbers were small, which is problematic when aiming to discriminate rare and complex diagnoses. In conclusion, the data indicate that AI has potential as a diagnostic decision support system, but clinical applicability is not yet established. Future studies and technologies need to incorporate more comprehensive clinical data and larger patient populations. In time, these should improve AI-based diagnostic tools and help clinicians diagnose, classify, and manage patients with uveitis.

Aim: To explore if novel non-invasive diagnostic technologies identify early small nerve fibre and retinal neurovascular pathology in prediabetes., Methods: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent an exploratory cross-sectional analysis with optical coherence tomography angiography (OCT-A), handheld electroretinography (ERG), corneal confocal microscopy (CCM) and evaluation of electrochemical skin conductance (ESC)., Results: Seventy-five participants with normoglycaemia (n = 20), prediabetes (n = 29) and type 2 diabetes (n = 26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16-Td·s: 4.05 μV, 95% confidence interval [95% CI] 0.96-7.13) and high (32-Td·s: 5·20 μV, 95% CI 1.54-8.86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm 2 , 95% CI 0.005-0.095) and deep (0.048 pixels/mm 2 , 95% CI 0.003-0.093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA 1c and peak ERG amplitude at 32-Td·s (r = -0.256, p = 0.028), implicit time at 32-Td·s (r = 0.422, p < 0.001) and 16-Td·s (r = 0.327, p = 0.005), OCT parafoveal vessel density in the superficial (r = -0.238, p = 0.049) and deep (r = -0.3, p = 0.017) retinal layers, corneal nerve fibre length (CNFL) (r = -0.293, p = 0.017), and ESC-hands (r = -0.244, p = 0.035) were observed. HOMA-IR was a predictor of CNFD (β = -0.94, 95% CI -1.66 to -0.21, p = 0.012) and CNBD (β = -5.02, 95% CI -10.01 to -0.05, p = 0.048)., Conclusions: The glucose threshold for the diagnosis of diabetes is based on emergent retinopathy on fundus examination. We show that both abnormal retinal neurovascular structure (OCT-A) and function (ERG) may precede retinopathy in prediabetes, which require confirmation in larger, adequately powered studies., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Agent-based models (ABMs) are an increasingly important tool for understanding the complexities presented by phenotypic and spatial heterogeneity in biological tissue. The resolution a modeler can achieve in these regards is unrivaled by other approaches. However, this comes at a steep computational cost limiting either the scale of such models or the ability to explore, parameterize, analyze, and apply them. When the models involve molecular-level dynamics, especially cell-specific dynamics, the limitations are compounded. We have developed a global method for solving these computationally expensive dynamics significantly decreases the computational time without altering the behavior of the system. Here, we extend this method to the case where cells can switch phenotypes in response to signals in the microenvironment. We find that the global method in this context preserves the temporal population dynamics and the spatial arrangements of the cells while requiring markedly less simulation time. We thus add a tool for efficiently simulating ABMs that captures key facets of the molecular and cellular dynamics in heterogeneous tissue., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bergman, Jackson. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Multiscale systems biology is having an increasingly powerful impact on our understanding of the interconnected molecular, cellular, and microenvironmental drivers of tumor growth and the effects of novel drugs and drug combinations for cancer therapy. Agent-based models (ABMs) that treat cells as autonomous decision-makers, each with their own intrinsic characteristics, are a natural platform for capturing intratumoral heterogeneity. Agent-based models are also useful for integrating the multiple time and spatial scales associated with vascular tumor growth and response to treatment. Despite all their benefits, the computational costs of solving agent-based models escalate and become prohibitive when simulating millions of cells, making parameter exploration and model parameterization from experimental data very challenging. Moreover, such data are typically limited, coarse-grained and may lack any spatial resolution, compounding these challenges. We address these issues by developing a first-of-its-kind method that leverages explicitly formulated surrogate models (SMs) to bridge the current computational divide between agent-based models and experimental data. In our approach, Surrogate Modeling for Reconstructing Parameter Surfaces (SMoRe ParS), we quantify the uncertainty in the relationship between agent-based model inputs and surrogate model parameters, and between surrogate model parameters and experimental data. In this way, surrogate model parameters serve as intermediaries between agent-based model input and data, making it possible to use them for calibration and uncertainty quantification of agent-based model parameters that map directly onto an experimental data set. We illustrate the functionality and novelty of Surrogate Modeling for Reconstructing Parameter Surfaces by applying it to an agent-based model of 3D vascular tumor growth, and experimental data in the form of tumor volume time-courses. Our method is broadly applicable to situations where preserving underlying mechanistic information is of interest, and where computational complexity and sparse, noisy calibration data hinder model parameterization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jain, Norton, Prado and Jackson.)

Background: Iron deficiency anemia (IDA) is common during pregnancy and associated with adverse maternal and neonatal outcomes. Treatment with iron supplementation is recommended during pregnancy, but the optimal delivery route is unclear. Oral iron risks has high risk of gastrointestinal side effects and low absorption. Intravenous iron is infused directly but is expensive. The American College of Obstetricians and Gynecologists currently recommends oral iron to treat IDA in pregnancy with intravenous iron reserved as second-line therapy, if needed. This approach is associated with persistent anemia, increasing the risk of peripartum blood transfusion. We aim to provide data on optimal route of iron repletion for IDA in pregnancy., Methods: In IVIDA2, a double-blind, placebo controlled, multicenter randomized trial in the United States, 746 pregnant people with moderate-to-severe IDA (hemoglobin <10 g/dL and ferritin <30 ng/mL) at 24-28 weeks' gestation will be randomized 1:1 to either a single 1000 mg dose of intravenous ferric derisomaltose and oral placebo (1-3 times daily) or a single placebo infusion with 1-3 times daily 325 mg ferrous sulfate (65 mg elemental iron) tablet. The primary outcome is peripartum blood transfusion (blood transfusion from delivery to 7 days postpartum). Secondary outcomes include adverse medication reactions, maternal and neonatal hematologic indices, and offspring neurodevelopment., Ethics and Dissemination: A central ethical review board-Advarra-granted ethical approval (Pro00060930). Participating centers-Women & Infants Hospital of Rhode Island, University of Michigan Medical Center, Washington University School of Ethics and dissemination: A central ethical review board-Advarra-granted ethical approval (Pro00060930). Participating centers-Women & Infants Hospital of Rhode Island, University of Michigan Medical Center, Washington University School of., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The study is funded by the NICHD (R01 HD105855; PI: Methodius Tuuli) and supported by an unrestricted grant from Pharmacosmos Therapeutics Inc. (MPI: Methodius Tuuli & Adam Lewkowitz). Neither NICHD nor Pharmacosmos Therapeutics, Inc has no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of this manuscript and the decision to submit for publication. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NICHD or Pharmacosmos Therapeutics Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This protocol explains how to take an agent-based model (ABM) with molecular dynamics and set it up to solve the molecular dynamics with a global approach. It can be used to speed up simulations significantly while retaining high levels of accuracy with the original ABM. Two options are presented for implementing this global approach, depending on the desired spatial variability in molecular concentrations. Both options coarse-grain the molecular dynamics in space by dividing the microenvironment into regions with uniform concentrations. For complete details on the use and execution of this protocol, please refer to Bergman et al. (2022)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Corneal confocal microscopy (CCM) is a rapid non-invasive in vivo ophthalmic imaging technique that images the cornea. Historically, it was utilised in the diagnosis and clinical management of corneal epithelial and stromal disorders. However, over the past 20 years, CCM has been increasingly used to image sub-basal small nerve fibres in a variety of peripheral neuropathies and central neurodegenerative diseases. CCM has been used to identify subclinical nerve damage and to predict the development of diabetic peripheral neuropathy (DPN). The complex structure of the corneal sub-basal nerve plexus can be readily analysed through nerve segmentation with manual or automated quantification of parameters such as corneal nerve fibre length (CNFL), nerve fibre density (CNFD), and nerve branch density (CNBD). Large quantities of 2D corneal nerve images lend themselves to the application of artificial intelligence (AI)-based deep learning algorithms (DLA). Indeed, DLA have demonstrated performance comparable to manual but superior to automated quantification of corneal nerve morphology. Recently, our end-to-end classification with a 3 class AI model demonstrated high sensitivity and specificity in differentiating healthy volunteers from people with and without peripheral neuropathy. We believe there is significant scope and need to apply AI to help differentiate between peripheral neuropathies and also central neurodegenerative disorders. AI has significant potential to enhance the diagnostic and prognostic utility of CCM in the management of both peripheral and central neurodegenerative diseases.