Early-life infection depletes preleukemic cells in a mouse model of hyperdiploid B-cell acute lymphoblastic leukemia.

Epidemiological studies report opposing influences of infection on childhood B cell acute lymphoblastic leukemia (B-ALL). Although infections in the first year of life appear to exert the largest impact on leukemia risk, the effect of early pathogen exposure on the fetal preleukemia cells (PLC) that lead to B-ALL has yet to be reported. Using cytomegalovirus as a model early-life infection, we show that virus exposure within one week of birth induces profound depletion of transplanted B-ALL cells in two mouse models and of in situ-generated PLC in Eu-ret mice. The age-dependent depletion of PLC results from an elevated STAT4-mediated cytokine response in neonates, with high levels of IL-12p40-driven IFN-g production inducing PLC death. Similar PLC depletion can be achieved in adult mice by impairing viral clearance. These findings provide mechanistic support for an inhibitory effect of early-life infection on B-ALL progression and could inform development of therapeutic or preventative approaches.

Deep Neural Networks for Automated Outer Plexiform Layer Subsidence Detection on Retinal OCT of Patients With Intermediate AMD.

Purpose: The subsidence of the outer plexiform layer (OPL) is an important imaging biomarker on optical coherence tomography (OCT) associated with early outer retinal atrophy and a risk factor for progression to geographic atrophy in patients with intermediate age-related macular degeneration (AMD). Deep neural networks (DNNs) for OCT can support automated detection and localization of this biomarker. Methods: The method predicts potential OPL subsidence locations on retinal OCTs. A detection module (DM) infers bounding boxes around subsidences with a likelihood score, and a classification module (CM) assesses subsidence presence at the B-scan level. Overlapping boxes between B-scans are combined and scored by the product of the DM and CM predictions. The volume-wise score is the maximum prediction across all B-scans. One development and one independent external data set were used with 140 and 26 patients with AMD, respectively. Results: The system detected more than 85% of OPL subsidences with less than one false-positive (FP)/scan. The average area under the curve was 0.94 ± 0.03 for volume-level detection. Similar or better performance was achieved on the independent external data set. Conclusions: DNN systems can efficiently perform automated retinal layer subsidence detection in retinal OCT images. In particular, the proposed DNN system detects OPL subsidence with high sensitivity and a very limited number of FP detections. Translational Relevance: DNNs enable objective identification of early signs associated with high risk of progression to the atrophic late stage of AMD, ideally suited for screening and assessing the efficacy of the interventions aiming to slow disease progression.

Synthesis and active manipulation of magnetic liquid beads.

We report the fabrication and characterisation of magnetic liquid beads with a solid magnetic shell and liquid core using microfluidic techniques. The liquid beads consist of a fluorinated oil core and a polymer shell with magnetite particles. The beads are generated in a flow-focusing polydimethylsiloxane (PDMS) device and cured by photo polymerisation. We investigated the response of the liquid beads to an external magnetic field by characterising their motion towards a permanent magnet. Magnetic sorting of liquid beads in a channel was achieved with 90% efficiency. The results show that the liquid beads can be controlled magnetically and have potential applications in digital microfluidics including nucleic acid amplification, drug delivery, cell culture, sensing, and tissue engineering. The present paper also discusses the magnetophoretic behaviour of the liquid bead by varying its mass and magnetite concentration in the shell. We also demonstrated the two-dimensional self-assembly of magnetic liquid beads for potential use in digital polymerase chain reaction and digital loop mediated isothermal amplification.

AI-based support for optical coherence tomography in age-related macular degeneration.

Artificial intelligence (AI) has emerged as a transformative technology across various fields, and its applications in the medical domain, particularly in ophthalmology, has gained significant attention. The vast amount of high-resolution image data, such as optical coherence tomography (OCT) images, has been a driving force behind AI growth in this field. Age-related macular degeneration (AMD) is one of the leading causes for blindness in the world, affecting approximately 196 million people worldwide in 2020. Multimodal imaging has been for a long time the gold standard for diagnosing patients with AMD, however, currently treatment and follow-up in routine disease management are mainly driven by OCT imaging. AI-based algorithms have by their precision, reproducibility and speed, the potential to reliably quantify biomarkers, predict disease progression and assist treatment decisions in clinical routine as well as academic studies. This review paper aims to provide a summary of the current state of AI in AMD, focusing on its applications, challenges, and prospects.

Deep Learning-Based Prediction of Individual Geographic Atrophy Progression from a Single Baseline OCT.

Objective: To identify the individual progression of geographic atrophy (GA) lesions from baseline OCT images of patients in routine clinical care. Design: Clinical evaluation of a deep learning-based algorithm. Subjects: One hundred eighty-four eyes of 100 consecutively enrolled patients. Methods: OCT and fundus autofluorescence (FAF) images (both Spectralis, Heidelberg Engineering) of patients with GA secondary to age-related macular degeneration in routine clinical care were used for model validation. Fundus autofluorescence images were annotated manually by delineating the GA area by certified readers of the Vienna Reading Center. The annotated FAF images were anatomically registered in an automated manner to the corresponding OCT scans, resulting in 2-dimensional en face OCT annotations, which were taken as a reference for the model performance. A deep learning-based method for modeling the GA lesion growth over time from a single baseline OCT was evaluated. In addition, the ability of the algorithm to identify fast progressors for the top 10%, 15%, and 20% of GA growth rates was analyzed. Main Outcome Measures: Dice similarity coefficient (DSC) and mean absolute error (MAE) between manual and predicted GA growth. Results: The deep learning-based tool was able to reliably identify disease activity in GA using a standard OCT image taken at a single baseline time point. The mean DSC for the total GA region increased for the first 2 years of prediction (0.80-0.82). With increasing time intervals beyond 3 years, the DSC decreased slightly to a mean of 0.70. The MAE was low over the first year and with advancing time slowly increased, with mean values ranging from 0.25 mm to 0.69 mm for the total GA region prediction. The model achieved an area under the curve of 0.81, 0.79, and 0.77 for the identification of the top 10%, 15%, and 20% growth rates, respectively. Conclusions: The proposed algorithm is capable of fully automated GA lesion growth prediction from a single baseline OCT in a time-continuous fashion in the form of en face maps. The results are a promising step toward clinical decision support tools for therapeutic dosing and guidance of patient management because the first treatment for GA has recently become available. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

mRNA Display Identifies Potent, Paralog-Selective Peptidic Ligands for ARID1B.

The ARID1A and ARID1B subunits are mutually exclusive components of the BAF variant of SWI/SNF chromatin remodeling complexes. Loss of function mutations in ARID1A are frequently observed in various cancers, resulting in a dependency on the paralog ARID1B for cancer cell proliferation. However, ARID1B has never been targeted directly, and the high degree of sequence similarity to ARID1A poses a challenge for the development of selective binders. In this study, we used mRNA display to identify peptidic ligands that bind with nanomolar affinities to ARID1B and showed high selectivity over ARID1A. Using orthogonal biochemical, biophysical, and chemical biology tools, we demonstrate that the peptides engage two different binding pockets, one of which directly involves an ARID1B-exclusive cysteine that could allow covalent targeting by small molecules. Our findings impart the first evidence of the ligandability of ARID1B, provide valuable tools for drug discovery, and suggest opportunities for the development of selective molecules to exploit the synthetic lethal relationship between ARID1A and ARID1B in cancer.

A Comparative Study of B Cell Blast Isolation Methods from Bone Marrow Aspirates of Pediatric Leukemia Patients.

Density gradient centrifugation is a conventional technique widely utilized to isolate bone marrow mononuclear cells (BM-MNC) from bone marrow (BM) aspirates obtained from pediatric B-cell acute lymphoblastic leukemia (B-ALL) patients. Nevertheless, this technique achieves incomplete recovery of mononuclear cells and is relatively time-consuming and expensive. Given that B-ALL is the most common childhood malignancy, alternative methods for processing B-ALL samples may be more cost-effective. In this pilot study, we use several readouts, including immune phenotype, cell viability, and leukemia-initiating capacity in immune-deficient mice, to directly compare the density gradient centrifugation and buffy coat processing methods. Our findings indicate that buffy coat isolation yields comparable BM-MNC product in terms of both immune and leukemia cell content and could provide a viable, lower cost alternative for biobanks processing pediatric leukemia samples.

Long-term impact of low-energy femtosecond laser and manual cataract surgery on macular layer thickness: A prospective randomized study.

PURPOSE: To evaluate change in retinal layers 18 months after femtosecond laser-assisted cataract surgery (LCS) and manual cataract surgery (MCS) in a representative age-related cataract population using artificial intelligence (AI)-based automated retinal layer segmentation. METHODS: This was a prospective, randomized and intraindividual-controlled study including 60 patients at the Medical University of Vienna, Austria. Bilateral same-day LCS and MCS were performed in a randomized sequence. To provide insight into the development of cystoid macular oedema (CME), retinal layer thickness was measured pre-operatively and up to 18 months post-operatively in the central 1 mm, 3 mm and 6 mm. RESULTS: Fifty-six patients completed all follow-up visits. LCS compared to MCS did not impact any of the investigated retinal layers at any follow-up visit (p > 0.05). For the central 1 mm, a significant increase in total retinal thickness (TRT) was seen after 1 week followed by an elevated plateau thereafter. For the 3 mm and 6 mm, TRT increased only after 3 weeks and 6 weeks and decreased again until 18 months. TRT remained significantly increased compared to pre-operative thickness (p < 0.001). Visual acuity remained unaffected by the macular thickening and no case of CME was observed. Inner nuclear layer (INL) and outer nuclear layer (ONL) were the main causative layers for the total TRT increase. Photoreceptors (PR) declined 1 week after surgery but regained pre-operative values 18 months after surgery. CONCLUSION: Low-energy femtosecond laser pre-treatment did not influence thickness of the retinal layers in any topographic zone compared to manual high fluidic phacoemulsification. TRT did not return to pre-operative values 18 months after surgery. The causative layers for subclinical development of CME were successfully identified.

Surgically induced astigmatism in the scleral fixated 'Carlevale' IOL technique.

PURPOSE: To evaluate the surgically induced astigmatism over a 6-month follow-up period in patients who underwent scleral IOL fixation using an acrylic single-piece IOL with special haptics designed for sutureless scleral fixation. METHODS: We conducted a prospective longitudinal study at a single site with a single surgeon. We included patients who received transscleral IOL implantation following the Carlevale technique and were followed up post-operatively for 24 weeks. We measured the patient's refraction at baseline, week 12 and week 24 using the best corrected visual acuity at 4 m (EDTRS chart). We performed corneal tomography at every visit using an anterior segment optical coherence tomography (AS-OCT). We evaluated surgically induced astigmatism (SIA) and refraction during each follow-up visit and compared them to baseline. We then assessed changes in SIA over time. RESULTS: In total, 27 eyes of 27 patients consisting of 16 female and 11 male individuals were evaluated. The mean patient age was 71 ± 11.7 years, mean axial length was 24.30 ± 1.47 mm (range: 21.4-27.23) and mean white-to-white distance was 12.07 ± 0.40 mm (range: 11.4-12.7). The mean SIA decreased from 1.78 ± 0.96D at week 1 significantly to 0.80 ± 0.55D at week 12 (p < 0.001) and then stayed unchanged around 0.82 ± 0.72D at week 24 (p = 1.0). CONCLUSIONS: The scleral fixated Carlevale IOL and its implantation procedure were found to result in a predictable SIA of <1D after 24 weeks. However, the axis orientation of the SIA appeared to be random, making it unsuitable for implementation in toric IOL calculations.

The Eµ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia.

The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eµ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eµ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eµ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.

A Systematic Prospective Comparison of Fluid Volume Evaluation across OCT Devices Used in Clinical Practice.

Objective: Treatment decisions in neovascular age-related macular degeneration (nAMD) are mainly based on subjective evaluation of OCT. The purpose of this cross-sectional study was to provide a comparison of qualitative and quantitative differences between OCT devices in a systematic manner. Design: Prospective, cross-sectional study. Subjects: One hundred sixty OCT volumes, 40 eyes of 40 patients with nAMD. Methods: Patients from clinical practice were imaged with 4 different OCT devices during one visit: (1) Spectralis Heidelberg; (2) Cirrus; (3) Topcon Maestro2; and (4) Topcon Triton. Intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED) were manually annotated in all cubes by trained human experts to establish fluid measurements based on expert-reader annotations. Intraretinal fluid, SRF, and PED volume were quantified in nanoliters (nL). Bland-Altman plots were created to analyze the agreement of measurements in the central 1 and 6 mm. The Friedman test was performed to test for significant differences in the central 1, 3, and 6 mm. Main Outcome Measures: Intraretinal fluid, SRF, and PED volume. Results: In the central 6 mm, there was a trend toward higher IRF and PED volumes in Spectralis images compared with the other devices and no differences in SRF volume. In the central 1 mm, the standard deviation of the differences ranged from ± 3 nL to ± 6 nL for IRF, from ± 3 nL to ± 4 nL for SRF, and from ± 7 nL to ± 10 nL for PED in all pairwise comparisons. Manually annotated IRF and SRF volumes showed no significant differences in the central 1 mm. Conclusions: Fluid volume quantification achieved excellent reliability in all 3 retinal compartments on images obtained from 4 OCT devices, particularly for clinically relevant IRF and SRF values. Although fluid volume quantification is reliable in all 4 OCT devices, switching OCT devices might lead to deviating fluid volume measurements with higher agreement in the central 1 mm compared with the central 6 mm, with highest agreement for SRF volume in the central 1 mm. Understanding device-dependent differences is essential for expanding the interpretation and implementation of pixel-wise fluid volume measurements in clinical practice and in clinical trials. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Structure-Function Correlation of Retinal Fibrosis in Eyes with Neovascular Age-Related Macular Degeneration.

Purpose: To assess retinal function in areas of presumed fibrosis due to neovascular age-related macular degeneration (nAMD), using multimodal imaging and structure-function correlation. Design: Cross-sectional observational study. Methods: 30 eyes of 30 consecutive patients with nAMD with a minimum history of one year of anti-vascular endothelial growth factor therapy were included. Each patient underwent microperimetry (MP), color fundus photography (CFP), standard spectral-domain-based OCT (SD-OCT), and polarization sensitive-OCT (PS-OCT) imaging. PS-OCT technology can depict retinal fibrosis based on its birefringence. CFP, SD-OCT, and PS-OCT were evaluated independently for the presence of fibrosis at the corresponding MP stimuli locations. MP results and morphologic findings in CFP, SD-OCT, and PS-OCT were co-registered and analyzed using mixed linear models. Results: In total, 1350 MP locations were evaluated to assess the functional impact of fibrosis according to a standardized protocol. The estimated means of retinal areas with signs of fibrosis were 12.60 db (95% confidence interval: 10.44-14.76) in CFP, 11.60 db (95% COI: 8.84-14.36) in OCT, and 11.02 db (95% COI 8.10-13.94) in PS-OCT. Areas evaluated as subretinal fibrosis in three (7.2 db) or two (10.1 db) modalities were significantly correlated with a lower retinal sensitivity than a subretinal fibrosis observed in only one (15.3 db) or none (23.3 db) modality (p < 0.001). Conclusions: CFP, SD-OCT and PS-OCT are all suited to detect areas of reduced retinal sensitivity related to fibrosis, however, a multimodal imaging approach provides higher accuracy in the identification of areas with low sensitivity in MP (i.e., impaired retinal function), and thereby improves the detection rate of subretinal fibrosis in nAMD.

Systemic delivery of mutant huntingtin lowering antisense oligonucleotides to the brain using apolipoprotein A-I nanodisks for Huntington disease.

Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD.

Inter and intradevice assessment of microperimetry testing in aging eyes.

Microperimetry (MP) is a psychometric examination combining retinal imaging and functional sensitivity testing with an increasing importance due to its potential use as clinical study outcome. We investigated the repeatability of pointwise retinal sensitivity (PWS) on the most advanced commercially available MP devices under their standard setting in a healthy aging population. Two successive MP examinations on both MP-3 (NIDEK CO., Ltd., Gamagori, Japan) and MAIA (CenterVue S.p.A. (iCare), Padova, Italy) were performed on healthy aging subjects in a randomized order. PWS repeatability was analysed for different macular regions and age groups using Bland-Altmann coefficients of repeatability (CoR). A total of 3600 stimuli from 20 healthy individuals with a mean age of 70 (11) years were included. Mean CoR in dB were ±4.61 for MAIA and ±4.55 for MP-3 examinations. A lower repeatability (p=0.005) was detected in the central millimetre on MAIA examinations. Higher subject age was associated with a lower repeatability of PWS on both devices (both p=0.003). Intra-device correlation was good (MAIA: 0.79 [0.76-0.81]; MP-3: 0.72 [0.68-0.76]) whereas a moderate mean inter-device correlation (0.6 [0.55-0.65]) could be detected. In conclusion, older subjects and the foveal region are associated with a worse pointwise repeatability.

Influence of drusenoid pigment epithelial detachments on the progression of age-related macular degeneration and visual acuity.

OBJECTIVE: To analyze the presence and morphologic characteristics of drusenoid pigment epithelial detachments (DPEDs) in spectral-domain optical coherence tomography (SD-OCT) in Caucasian patients with early and intermediate age-related macular degeneration (AMD) as well as the influence of these characteristics on best-corrected visual acuity (BCVA) and disease progression. DESIGN: Prospective observational cohort study. PARTICIPANTS: 89 eyes of 56 patients with early and intermediate AMD. METHODS: Examinations consisted of BCVA, SD-OCT, and indocyanine green angiography. Evaluated parameters included drusen type, mean drusen height and -volume, the presence of DPED, DPED maximum height, -maximum diameter, -volume, topographic location, the rate of DPED collapse, and the development of macular neovascularization (MNV) or geographic atrophy (GA). RESULTS: DPED maximum height (162.34 µm ± 75.70 µm, p = 0.019) was significantly associated with the development of GA and MNV. For each additional 100 µm in maximum height, the odds of developing any late AMD (GA or MNV) increased by 2.23 (95% CI = 1.14-4.35). The presence of DPED (44 eyes, p = 0.01), its volume (0.20 mm ± 0.20 mm, p = 0.01), maximum diameter (1860.87 µm ± 880.74 µm, p = 0.03), maximum height (p < 0.001) and topographical location in the central millimetre (p = 0.004) of the Early Treatment Diabetic Retinopathy Study (ETDRS)-Grid were significantly correlated with BCVA at the last follow-up (0.15logMAR ± 0.20logMAR; Snellen equivalent approximately 20/28). DPEDs occurred significantly less in the outer quadrants than in the central millimetre and inner quadrants of ETDRS-Grid (all p values < 0.001). CONCLUSIONS: The height of drusen and DPEDs is a biomarker that is significantly associated with the development of late AMD and visual loss. DPEDs affect predominantly the center and inner quadrants of the ETDRS-Grid.

Automated deep learning-based AMD detection and staging in real-world OCT datasets (PINNACLE study report 5).

Real-world retinal optical coherence tomography (OCT) scans are available in abundance in primary and secondary eye care centres. They contain a wealth of information to be analyzed in retrospective studies. The associated electronic health records alone are often not enough to generate a high-quality dataset for clinical, statistical, and machine learning analysis. We have developed a deep learning-based age-related macular degeneration (AMD) stage classifier, to efficiently identify the first onset of early/intermediate (iAMD), atrophic (GA), and neovascular (nAMD) stage of AMD in retrospective data. We trained a two-stage convolutional neural network to classify macula-centered 3D volumes from Topcon OCT images into 4 classes: Normal, iAMD, GA and nAMD. In the first stage, a 2D ResNet50 is trained to identify the disease categories on the individual OCT B-scans while in the second stage, four smaller models (ResNets) use the concatenated B-scan-wise output from the first stage to classify the entire OCT volume. Classification uncertainty estimates are generated with Monte-Carlo dropout at inference time. The model was trained on a real-world OCT dataset, 3765 scans of 1849 eyes, and extensively evaluated, where it reached an average ROC-AUC of 0.94 in a real-world test set.

Long-term effect of fluid volumes during the maintenance phase in neovascular age-related macular degeneration: results from Fight Retinal Blindness!

OBJECTIVE: To investigate the effect of macular fluid volumes (subretinal fluid [SRF], intraretinal fluid [IRF], and pigment epithelium detachment [PED]) after initial treatment on functional and structural outcomes in neovascular age-related macular degeneration in a real-world cohort from Fight Retinal Blindness! METHODS: Treatment-naive neovascular age-related macular degeneration patients from Fight Retinal Blindness! (Zürich, Switzerland) were included. Macular fluid on optical coherence tomography was automatically quantified using an approved artificial intelligence algorithm. Follow-up of macular fluid, number of anti-vascular endothelial growth factor treatments, effect of fluid volumes after initial treatment (high, top 25%; low, bottom 75%) on best-corrected visual acuity, and development of macular atrophy and fibrosis was investigated over 48 months. RESULTS: A total of 209 eyes (mean age, 78.3 years) were included. Patients with high IRF volumes after initial treatment differed by -2.6 (p = 0.021) and -7.4 letters (p = 0.007) at months 12 and 48, respectively. Eyes with high IRF received significantly more treatments (+1.6 [p < 0.001] and +5.3 [p = 0.002] at months 12 and 48, respectively). Patients with high SRF or PED had comparable best-corrected visual acuity outcomes but received significantly more treatments for SRF (+2.4 [p < 0.001] and +11.4 [p < 0.001] at months 12 and 48, respectively) and PED (+1.2 [p = 0.001] and +7.8 [p < 0.001] at months 12 and 48, respectively). DISCUSSION: Patients with high macular fluid after initial treatment are at risk of losing vision that may not be compensable with higher treatment frequency for IRF. Higher treatment frequency for SRF and PED may result in comparable treatment outcomes. Quantification of macular fluid in all compartments is essential to detect eyes at risk of aggressive disease.

Targetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) genomes show that relapses often arise from subclonal outgrowths. However, the impact of clonal evolution on the actionable proteome and response to targeted therapy is not known. Here, we present a comprehensive retrospective analysis of paired ALL diagnosis and relapsed specimen. Targeted next generation sequencing and proteome analysis indicate persistence of actionable genome variants and stable proteomes through disease progression. Paired viably-frozen biopsies show high correlation of drug response to variant-targeted therapies but in vitro selectivity is low. Proteome analysis prioritizes PARP1 as a pan-ALL target candidate needed for survival following cellular stress; diagnostic and relapsed ALL samples demonstrate robust sensitivity to treatment with two PARP1/2 inhibitors. Together, these findings support initiating prospective precision oncology approaches at ALL diagnosis and emphasize the need to incorporate proteome analysis to prospectively determine tumor sensitivities, which are likely to be retained at disease relapse.

Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B-cell precursor populations.

Common infections have long been proposed to play a role in the development of pediatric B-cell acute lymphoblastic leukemia (B-ALL). However, epidemiologic studies report contradictory effects of infection exposure on subsequent B-ALL risk, and no specific pathogen has been definitively linked to the disease. A unifying mechanism to explain the divergent outcomes could inform disease prevention strategies. We previously reported that the pattern recognition receptor (PRR) ligand Poly(I:C) exerted effects on B-ALL cells that were distinct from those observed with other nucleic acid-based PRR ligands. Here, using multiple double-stranded RNA (dsRNA) moieties, we show that the overall outcome of exposure to Poly(I:C) reflects the balance of opposing responses induced by its ligation to endosomal and cytoplasmic receptors. This PRR response biology is shared between mouse and human B-ALL and can increase leukemia-initiating cell burden in vivo during the preleukemia phase of B-ALL, primarily through tumor necrosis factor α signaling. The age of the responding immune system further influences the impact of dsRNA exposure on B-ALL cells in both mouse and human settings. Overall, our study demonstrates that potentially proleukemic and antileukemic effects can each be generated by the stimulation of pathogen recognition pathways and indicates a mechanistic explanation for the contrasting epidemiologic associations reported for infection exposure and B-ALL.

Approved AI-based fluid monitoring to identify morphological and functional treatment outcomes in neovascular age-related macular degeneration in real-world routine (FRB!).

AIM: To predict antivascular endothelial growth factor (VEGF) treatment requirements, visual acuity and morphological outcomes in neovascular age-related macular degeneration (nAMD) using fluid quantification by artificial intelligence (AI) in a real-world cohort. METHODS: Spectral-domain optical coherence tomography data of 158 treatment-naïve patients with nAMD from the Fight Retinal Blindness! registry in Zurich were processed at baseline, and after initial treatment using intravitreal anti-VEGF to predict subsequent 1-year and 4-year outcomes. Intraretinal and subretinal fluid and pigment epithelial detachment volumes were segmented using a deep learning algorithm (Vienna Fluid Monitor, RetInSight, Vienna, Austria). A predictive machine learning model for future treatment requirements and morphological outcomes was built using the computed set of quantitative features. RESULTS: Two hundred and two eyes from 158 patients were evaluated. 107 eyes had a lower median (≤7) and 95 eyes had an upper median (≥8) number of injections in the first year, with a mean accuracy of prediction of 0.77 (95% CI 0.71 to 0.83) area under the curve (AUC). Best-corrected visual acuity at baseline was the most relevant predictive factor determining final visual outcomes after 1 year. Over 4 years, half of the eyes had progressed to macular atrophy (MA) with the model being able to distinguish MA from non-MA eyes with a mean AUC of 0.70 (95% CI 0.61 to 0.79). Prediction for subretinal fibrosis reached an AUC of 0.74 (95% CI 0.63 to 0.81). CONCLUSIONS: The regulatory approved AI-based fluid monitoring allows clinicians to use automated algorithms in prospectively guided patient treatment in AMD. Furthermore, retinal fluid localisation and quantification can predict long-term morphological outcomes.