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A test particle orbit around an eccentric binary has two stationary states in which there is no nodal precession: coplanar and polar. Nodal precession of a misaligned test particle orbit centres on one of these stationary states. A low mass circumbinary disc undergoes the same precession and moves towards one of these states through dissipation within the disc. For a massive particle orbit, the stationary polar alignment occurs at an inclination less than $90^{\circ}$, this is the prograde-polar stationary inclination. A sufficiently high angular momentum particle has an additional higher inclination stationary state, the retrograde-polar stationary inclination. Misaligned particle orbits close to the retrograde-polar stationary inclination are not nested like the orbits close to the other stationary points. We investigate the evolution of a gas disc that begins close to the retrograde-polar stationary inclination. With hydrodynamical disc simulations, we find that the disc moves through the unnested crescent shape precession orbits and eventually moves towards the prograde-polar stationary inclination thus increasing the parameter space over which circumbinary discs move towards polar alignment. If protoplanetary discs form with an isotropic orientation relative to the binary orbit, then polar discs may be more common than coplanar discs around eccentric binaries, even for massive discs. This has implications for the alignment of circumbinary planets., Comment: Accepted for publication in MNRAS. 12 pages, 7 figures

Enhancing CRISPR-mediated site-specific transgene insertion efficiency by homology-directed repair (HDR) using high concentrations of double-stranded DNA (dsDNA) with Cas9 target sequences (CTSs) can be toxic to primary cells. Here, we develop single-stranded DNA (ssDNA) HDR templates (HDRTs) incorporating CTSs with reduced toxicity that boost knock-in efficiency and yield by an average of around two- to threefold relative to dsDNA CTSs. Using small-molecule combinations that enhance HDR, we could further increase knock-in efficiencies by an additional roughly two- to threefold on average. Our method works across a variety of target loci, knock-in constructs and primary human cell types, reaching HDR efficiencies of >80-90%. We demonstrate application of this approach for both pathogenic gene variant modeling and gene-replacement strategies for IL2RA and CTLA4 mutations associated with Mendelian disorders. Finally, we develop a good manufacturing practice (GMP)-compatible process for nonviral chimeric antigen receptor-T cell manufacturing, with knock-in efficiencies (46-62%) and yields (>1.5 × 109 modified cells) exceeding those of conventional approaches.

Background Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. Methods We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. Results The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. Conclusions Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity. This study was conducted within the CODATwins project. Support for collaborators: Colorado Twin Registry is funded by NIDA funded center grant DA011015, & Longititudinal Twin Study HD10333; Author Huibregtse is supported by National Institute on Drug Abuse (5T32DA017637) and National Institute on Aging (5T32AG052371). Finnish Twin Cohort is supported by the Academy of Finland (grants 312073 and 336823) and the Sigrid Juselius Foundation. Michigan State University Twin Registry was supported by National Institute of Mental Health (NIMH) (R01-MH081813, R01-MH0820–54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01, 1R01-MH118848-01), Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) (R01-HD066040) and MSU Foundation (11-SPG-2518). PETS was funded by the Australian National Health and Medical Research Council (grant numbers 437015 and 607358); the Bonnie Babes Foundation (grant number BBF20704); the Financial Markets Foundation for Children (grant number 032-2007); and the Victorian Government’s Operational Infrastructure Support Program. We acknowledge The Swedish Twin Registry for access to data. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. TEDS was supported by a program grant to RP from the UK Medical Research Council (MR/M021475/1 and previously G0901245), with additional support from the US National Institutes of Health (AG046938). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 20H04019) from the Japan Society for the Promotion of Science. Open Access funding provided by University of Helsinki including Helsinki University Central Hospital.

Background Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder but little is known about the genetic characterisation of this heterogeneity. Understanding the genetic etiology of MDD can be challenging as large sample sizes are needed for gene discovery – often achieved with a trade-off in the depth phenotyping. Methods The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom, met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest depression GWAS to date and subsequently used polygenic scores (PGS) to investigate genetic heterogeneity across various clinical subtypes of MDD. Results We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We show that a PGS for depression explains 5.7% of variance in MDD liability in our sample. Lastly, we find strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course and various subtypes of MDD. Conclusions Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with discovery of novel loci, we provide support for differential pathways to illness models that recognize both the overlap with other common psychiatric disorders, as well as pathophysiological differences.

Previous studies have demonstrated associations between substance use and reduced educational attainment; however, many were unable to account for potential confounding factors like genetics and the rearing environment. In the few studies that controlled for these factors, the substances assessed were limited to alcohol, cannabis, and tobacco. To address these limitations, we examined the relationship between adolescent use of seven kinds of substances, the number of additional substances used, and high school noncompletion within a large sample of Australian twins.A series of two-level generalized mixed effects logistic regressions were conducted to examine associations between adolescent substance use and high school noncompletion.Australia.A total of 9579 adult Australian twins from two cohorts of the Australian Twin Registry.Assessments of high school completion, childhood major depression, conduct disorder symptoms, substance use initiation, demographics, and parental educational attainment using the Australian version of the Semi-Structured Assessment for the Genetics of Alcoholism.There were unique within-twin-pair effects of use of sedatives (odds ratio [OR] = 22.39 [95% confidence interval (CI) = 1.18-423.48]) and inhalants/solvents (OR = 10.46 [95% CI = 1.30-84.16]) on high school noncompletion. The number of substances used in adolescence was strongly associated with high school noncompletion across all discordant twin models (ORs from 1.50-2.32, Ps0.03).In Australia, adolescent substance use appears to be associated with early school dropout, with the effects of any given substance largely because of the confounding factors of parental education, childhood conduct disorder symptoms, and use of other substances. Sedatives and inhalants/solvents have effects on high school noncompletion that cannot be explained by polysubstance use or familial factors.

Aseptic meningitis, including culture negative and viral meningitis, contributes a significant health-care burden, including unnecessary antibiotic use and hospitalisation to treat possible bacterial meningitis. This study analysed aseptic meningitis hospitalisations in New Zealand (NZ) children over 29 years.In this population-based study, aseptic meningitis hospitalisations in NZ children15 years old were analysed from 1991 to 2020. Incident rate ratios were calculated using Poisson regression models. Variations in hospitalisations by age, year, sex, ethnicity, geographical region and socio-economic deprivation were analysed.There were 5142 paediatric aseptic meningitis hospitalisations from 1991 to 2020. Most were unspecified viral meningitis (64%), followed by enterovirus (29%). Hospitalisation rates varied annually with a median of 18.4/100 000 children including a peak in 2001 of 56.4/100 000 (51.7-61.6). From 2002 to 2019, rates increased by 8.4%/year (7.2-9.5%) in infants90 days old but decreased in all other age groups. In 2020, a reduction in hospitalisations to 9.6/100 000 (7.9-11.8) occurred, and in infants90 days old were 0.37 times expected. Hospitalisations were 1.50 times (1.49-1.68) higher in males than females; higher in children of Māori (P 0.001) and Pacific (P 0.001) versus European ethnicity; and higher for children living in the most (2.44 times, (2.16-2.75)) versus least deprived households; and in northern versus southern NZ.Aseptic meningitis hospitalisations increased in young infants during 29 years of surveillance, apart from 2020 when admissions reduced during the COVID-19 pandemic. In contrast, hospitalisations decreased in children aged1 year. Further investigation into reasons for higher admissions by ethnic group, geographical location and increased deprivation are required.

KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER

The digitalization of industrial processes with e.g. the goal to increase the availability of production processes in general and to support the individualization of many products in particular leads to an increasing demand in sensor data. The state of the art for condition monitoring of involute gear trains is the measurement of structure-borne vibration with acceleration sensors. New approaches, such as measuring the instantaneous angular speed (IAS), are gaining in popularity. Machine manufacturers usually wish to use existing sensors or measurement points, where little or no effort is needed to implement the sensor concept. Magnetoresistive (MR) sensors fulfil this complex set of requirements to a high degree: They are comparatively easy to integrate, can be added as an optional component and provide sufficient accuracy.The authors have developed different sensor concepts using MR sensors for measuring IAS in a 1-stage helical gear box. Multiple tests with artificial tooth flank damages have been carried out to evaluate the damage detection potential of the sensor concepts. Finally, a spectrum analysis of the first gear mesh frequency and surrounding sidebands demonstrates the capability for detecting tooth flank damage with different MR sensor concepts.

Electrical potential differences across lipid bilayers play foundational roles in cellular physiology. Plasma membrane voltage is the most widely studied; however, the bilayers of organelles like mitochondria, lysosomes, nuclei, and the endoplasmic reticulum (ER) also provide opportunities for ionic compartmentalization and the generation of transmembrane potentials. Unlike plasma membranes, organellar bilayers, cloistered within the cell, remain recalcitrant to traditional approaches like patch-clamp electrophysiology. To address the challenge of monitoring changes in organelle membrane potential, we describe the design, synthesis, and application of the LUnAR RhoVR (

Rationale and Objectives Limited exposure to radiology by medical students can perpetuate negative stereotypes and hamper recruitment efforts. The purpose of this study is to understand medical students’ perceptions of radiology and how they change based on medical education and exposure. Materials and Methods A single-institution mixed-methods study included four groups of medical students with different levels of radiology exposure. All participants completed a 16-item survey regarding demographics, opinions of radiology, and perception of radiology stereotypes. Ten focus groups were administered to probe perceptions of radiology. Focus groups were coded to identify specific themes in conjunction with the survey results. Results Forty-nine participants were included. Forty-two percent of participants had positive opinions of radiology. Multiple radiology stereotypes were identified, and false stereotypes were diminished with increased radiology exposure. Opinions of the impact of artificial intelligence on radiology closely aligned with positive or negative views of the field overall. Multiple barriers to applying for a radiology residency position were identified including board scores and lack of mentorship. COVID-19 did not affect perceptions of radiology. There was broad agreement that students do not enter medical school with many preconceived notions of radiology, but that subsequent exposure was generally positive. Exposure both solidified and eliminated various stereotypes. Finally, there was general agreement that radiology is integral to the health system with broad exposure on all services. Conclusion Medical student perceptions of radiology are notably influenced by exposure and radiology programs should take active steps to engage in medical student education.

The hippocampus is a complex brain structure with key roles in cognitive and emotional processing and with subregion abnormalities associated with a range of disorders and psychopathologies. Here we combine data from two large independent young adult twin/sibling cohorts to obtain the most accurate estimates to date of genetic covariation between hippocampal subfield volumes and the hippocampus as a single volume. The combined sample included 2148 individuals, comprising 1073 individuals from 627 families (mean age = 22.3 years) from the Queensland Twin IMaging (QTIM) Study, and 1075 individuals from 454 families (mean age = 28.8 years) from the Human Connectome Project (HCP). Hippocampal subfields were segmented using FreeSurfer version 6.0 (CA4 and dentate gyrus were phenotypically and genetically indistinguishable and were summed to a single volume). Multivariate twin modeling was conducted in OpenMx to decompose variance into genetic and environmental sources. Bivariate analyses of hippocampal formation and each subfield volume showed that 10%–72% of subfield genetic variance was independent of the hippocampal formation, with greatest specificity found for the smaller volumes; for example, CA2/3 with 42% of genetic variance being independent of the hippocampus; fissure (63%); fimbria (72%); hippocampus-amygdala transition area (41%); parasubiculum (62%). In terms of genetic influence, whole hippocampal volume is a good proxy for the largest hippocampal subfields, but a poor substitute for the smaller subfields. Additive genetic sources accounted for 49%–77% of total variance for each of the subfields in the combined sample multivariate analysis. In addition, the multivariate analyses were sufficiently powered to identify common environmental influences (replicated in QTIM and HCP for the molecular layer and CA4/dentate gyrus, and accounting for 7%–16% of total variance for 8 of 10 subfields in the combined sample). This provides the clearest indication yet from a twin study that factors such as home environment may influence hippocampal volumes (albeit, with caveats).

Biomarkers may be useful endophenotypes for genetic studies if they share genetic sources of variation with the outcome, for example, with all-cause mortality. Australian adult study participants who had reported their parental survival information were included in the study: 14,169 participants had polygenic risk scores (PRS) from genotyping and up to 13,365 had biomarker results. We assessed associations between participants’ biomarker results and parental survival, and between biomarker results and eight parental survival PRS at varying p-value cut-offs. Survival in parents was associated with participants’ serum bilirubin, C-reactive protein, HDL cholesterol, triglycerides and uric acid, and with LDL cholesterol for participants’ fathers but not for their mothers. PRS for all-cause mortality were associated with liver function tests (alkaline phosphatase, butyrylcholinesterase, gamma-glutamyl transferase), metabolic tests (LDL and HDL cholesterol, triglycerides, uric acid), and acute-phase reactants (C-reactive protein, globulins). Association between offspring biomarker results and parental survival demonstrates the existence of familial effects common to both, while associations between biomarker results and PRS for mortality favor at least a partial genetic cause of this covariation. Identification of genetic loci affecting mortality-associated biomarkers offers a route to the identification of additional loci affecting mortality.

Our diagnostic radiology (DR) program lacked a formalized, structured process for residents to learn from errors. Prior DR residency Accreditation Council for Graduate Medical Education (ACGME) survey results additionally demonstrated opportunity for improvement in resident evaluation, resources, and patient safety/teamwork. Our project's purpose was to implement and evaluate a new resident-oriented radiology morbidity and mortality (MM) conference to enhance resident education.All DR residents (n = 48) were surveyed regarding a new didactic MM consisting of quarterly resident-led and faculty-moderated MMs. Cases for potential review were collected and stored in a REDCap database via an anonymous survey, from which resident-selected faculty curators would select 4-6 for presentation. Residents presented these cases and the group discussed applicable improvements. An anonymous survey of residents followed each conference. Relevant questions from ACGME survey data were extracted from the two years preceding the didactic MM and the pilot year.Before implementation, 86% of responding residents (n = 29; 60% of resident complement) supported the program, 90% expressed willingness to share their own mistakes, and 79% preferred faculty involvement. Respondents favored careful selection of faculty to promote education. At one year, 100% of respondents (n = 17; 35% of resident complement) approved of adding the didactic MM and endorsed program continuance. All respondents expressed a willingness to share their own mistakes. There was also coincident improvement in ACGME survey data in the domains of evaluation, resources, and patient safety/teamwork.We designed and implemented a resident-oriented MM conference that resulted in increased resident confidence and impacted ACGME survey results in evaluation, resources, and patient safety/teamwork.Implementation of a structured, resident-oriented radiology MM conference can increase resident confidence and impact ACGME survey results in the domains of evaluation, resources, and patient safety/teamwork.

It is widely recognized that dizygotic twinning (DZT) runs in families, but estimates of heritability from twin and family data are remarkably scarce and vary considerably. Here, we traced seven large, sometimes historical, multigeneration pedigrees from West Africans, fin de siècle French Jews, Canadians (two pedigrees), and the French royal family, in which twin births were recorded. We estimated heritability of twinning (of all types) as zygosity information was not available, diluting the true DZT heritability by a third or so. The estimates in the range 8−20% are remarkably consistent across time (8−19 generations) and ethnicities and also consistent with twin and family estimates.

Superorbital periods are observed in the optical light curves of many Be/X-ray binaries yet their origin has remained somewhat elusive. We suggest that precession of the spin axis of the Be star can drive superorbital periods, particularly for short orbital period binaries. We consider the short orbital period ($P_{\rm orb}=16.6\,\rm day$) and highly eccentric ($e_{\rm b}=0.72$) Be/X-ray binary A0538-66 that has a superorbital period of $421\,\rm day$. First we show that the spin axis precession timescale is about twice the observed superorbital period. Then, with hydrodynamic simulations we show that the Be star decretion disc can remain locked to the equator of the precessing Be star. At each periastron passage of the neutron star, material is accreted into a disc around the neutron star. The neutron star disc nodally precesses on the same timescale as the Be star disc and therefore both discs can contribute to the observed superorbital period. For wider and less eccentric binary systems, the Be star disc can have a larger radial extent and more complex behaviour is expected as a result of disc warping and breaking., Accepted for publication in MNRAS Letters

The recruitment of participants for research studies may be subject to bias due to an overrepresentation of those more willing to participate voluntarily. No study has analysed the effect of genetic predisposition to Alzheimer’s disease (AD) on study participation. The Prospective Imaging Study of Ageing (PISA), aims to characterise the phenotype and natural history of healthy adult Australians at high future risk of AD. Participants approached to take part in PISA were selected from existing cohort studies with available genome-wide genetic data for both successfully and unsuccessfully recruited participants, allowing us to investigate the genetic contribution to voluntary recruitment. From a recruitment pool of 13,432 individuals (age 40-80), 64% of participants were successfully recruited into the study. Polygenic risk scores (PRS) were computed in order to test to what extent the genetic risk for AD, and related risk factors (including educational attainment, household income and IQ), predicted participation in PISA. We examined the associations between PRS andAPOEε4 with recruitment using logistic regression models. We found significant associations of age and sex with study participation, where older and female participants were more likely to complete the core module. We did not identify a significant association of genetic risk for AD with study participation. Nonetheless, we identified significant associations with genetic scores for key causal risk factors for AD, such as IQ, household income and years of education. Our findings highlight the importance of considering bias in key risk factors for AD in the recruitment of individuals for cohort studies.

Recurrence is a critical aspect of breast cancer (BC) that is inexorably tied to mortality. Reuse of healthcare data through Machine Learning (ML) algorithms offers great opportunities to improve the stratification of patients at risk of cancer recurrence. We hypothesized that combining features from structured and unstructured sources would provide better prediction results for 5-year cancer recurrence than either source alone. We collected and preprocessed clinical data from a cohort of BC patients, resulting in 823 valid subjects for analysis. We derived three sets of features: structured information, features from free text, and a combination of both. We evaluated the performance of five ML algorithms to predict 5-year cancer recurrence and selected the best-performing to test our hypothesis. The XGB (eXtreme Gradient Boosting) model yielded the best performance among the five evaluated algorithms, with precision = 0.900, recall = 0.907, F1-score = 0.897, and area under the receiver operating characteristic AUROC = 0.807. The best prediction results were achieved with the structured dataset, followed by the unstructured dataset, while the combined dataset achieved the poorest performance. ML algorithms for BC recurrence prediction are valuable tools to improve patient risk stratification, help with post-cancer monitoring, and plan more effective follow-up. Structured data provides the best results when fed to ML algorithms. However, an approach based on natural language processing offers comparable results while potentially requiring less mapping effort. European Union | Ref. 875406 Fondo Europeo de Desarrollo Regional (FEDER) Xunta de Galicia

Parkinson’s disease (PD) is a late-onset and genetically complex neurodegenerative disorder. Here we sought to identify genes and molecular pathways underlying the associations between PD and the volume of ten brain structures measured through magnetic resonance imaging (MRI) scans. We leveraged genome-wide genetic data from several cohorts, including the International Parkinson’s Disease Genomics Consortium (IPDG), the UK Biobank, the Adolescent Brain Cognitive Development (ABCD) study, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the Enhancing Neuroimaging Genetics through Meta-Analyses (ENIGMA), and 23andMe. We observed significant positive genetic correlations between PD and intracranial and subcortical brain volumes. Genome-wide association studies (GWAS) - pairwise analyses identified 210 genomic segments with shared aetiology between PD and at least one of these brain structures. Pathway enrichment results highlight potential links with chronic inflammation, the hypothalamic-pituitary-adrenal pathway, mitophagy, disrupted vesicle-trafficking, calcium-dependent, and autophagic pathways. Investigations for putative causal genetic effects suggest that a larger putamen volume could influence PD risk, independently of the potential causal genetic effects of intracranial volume (ICV) on PD. Our findings suggest that genetic variants influencing larger intracranial and subcortical brain volumes, possibly during earlier stages of life, influence the risk of developing PD later in life.

Observations across the electromagnetic spectrum of radiative processes involving interstellar dust -- emission, extinction, and scattering -- are used to constrain the parameters of dust models and more directly to aid in foreground removal of dust for extragalactic and cosmology observations. The more complementary observations, the better. Here, we quantify the relationship between scattered light and thermal emission from dust in a diffuse (cirrus) intermediate latitude cloud, Spider, using data from the Dragonfly Telephoto Array and the Herschel Space Observatory. A challenge for optical observations of faint cirrus is accurate removal of a contaminating spatially varying sky background. We present a technique to analyse two images of the same cirrus field concurrently, correlating pixel values to capture the relationship and simultaneously fitting the sky background as a complex non-correlating additive component. For the Spider, we measure a $g-r$ color of 0.644$\pm 0.024$ and a visible wavelength to 250 $\mu$m intensity ratio of $10^{-3} \times (0.855 \pm0.025)$ and $10^{-3} \times (1.55\pm0.08)$ for $g$ and $r$-band respectively. We show how to use any dust model that matches the thermal dust emission to predict an upper limit to the amount of scattered light. The actual brightness of the cirrus will be fainter than this limit because of anisotropic scattering by the dust combined with anisotropy of the incident interstellar radiation field (ISRF). Using models of dust and the ISRF in the literature we illustrate that the predicted brightness is indeed lower, though not as faint as the observations indicate., Comment: 12 pages, 6 figures, The Astrophysical Journal

Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

Acute myeloid leukemia (AML) patients refractory to induction therapy or relapsed within 1 year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in preclinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single-cell RNA sequencing using prospectively acquired patient specimens identified IFN response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well tolerated, with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.Significance:This study demonstrates a favorable safety profile and promising clinical activity of ficlatuzumab and cytarabine in high-risk AML, thus supporting further investigation of this combination in a randomized trial. It also shows the utility of a novel application using multiplexed single-cell analyses to detect on-target activity and identify biomarkers of response.This article is highlighted in the In This Issue feature, p. 403

Supplementary Data from Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis

BCMA bispecific is highly active in vivo.

Tables show PK kinetics, plasma cell numbers, and patient data. Methods include all supplemental methods.

Supplementary Figure S1:Effect of CB-5083 on cell growth and survival in multiple myeloma and solid tumor cell lines; Supplementary Figure S2:CB-5083 activates UPR;Supplementary Figure S3:CB-5083 transcriptional response is unique in comparison to proteasome inhibitors;Supplementary Figure S4:CB-5083 enhances the antitumor activity of proteasome inhibitors; Supplementary Figure S5: Nrf1 upregulation induced by bortezomib is inhibited by CB-5083; Supplementary Figure S6:CB-5083 demonstrates a broad activity in multiple myeloma relevant in vivo models; Supplementary Table S1: List of antibodies used in the manuscript.