Publications by Year: 2026

Sex differences in spatial abilities, such as the capacity to mentally rotate objects and manipulate them in space, are well-documented, typically emerging around age 13, with males consistently showing an advantage in response speed over females. However, little is known about the sex differences in the development of object imagery ability—the ability to mentally visualize the appearance of objects in terms of color and shape. Given neuroscience evidence that the ventral pathway, associated with object imagery, develops differently from the dorsal pathway involved in spatial processing, we hypothesized that the development of sex differences would vary between these two domains. In this study, we examined the development of three components of object imagery ability (shape, color, and texture) across four different age groups (13, 14, 15, and adults aged 18–35). A sample of 514 secondary school students from Singapore and 323 adults from the National University of Singapore were administered a series of spatial and object imagery tests. Females outperformed males in texture and shape imagery, and these differences remained consistent across all age groups and in adults, independent of specialization, suggesting a developmental pattern distinct from spatial ability.

Longitudinal studies are required to measure individual differences in human brain aging, but are challenging over short intervals due to measurement error. Using cluster scanning, an approach that reduces error by densely repeating rapid structural scans, we assess brain aging in individuals across three timepoints in one year. Cluster scanning substantially improves the precision of individualized estimates, revealing previously undetectable individual differences in brain change. In just one year, we detect expected differences in the rates of brain aging between younger and older individuals, as well as differences between cognitively unimpaired and impaired individuals. Cognitively unimpaired older individuals variably reveal relative brain maintenance, unexpectedly rapid decline, and asymmetrical changes. We observe these atypical brain aging trajectories across structures and verify them in independent within-individual test-retest data. Cluster scanning promises to advance our understanding of the marked heterogeneity in brain aging by affording better short-term tracking of individual variability in structural change.

Pancreatic ductal adenocarcinoma (PDAC) has a relatively low incidence but a high mortality rate, primarily due to difficulties in early detection. Current state-of-the-art methods for diagnosing early-stage PDAC tend to be invasive, time-consuming, and unreliable, primarily due to the difficulties associated with the early detection of pancreatic cancers. Here we show a quick and sensitive method for the early diagnosis of PDAC using a signal-enhanced lateral flow immunoassay called SELFI. We develop SELFI, which generates a strong colorimetric signal through multiple hotspots formed by plasmonic gold nanoparticles (AuNPs) assembled on a silica nanoparticle. Our SELFI assay achieves a 10,123-fold increase in the limit of detection compared to conventional lateral flow immunoassays using 20 nm AuNPs, providing results within 15 min. We demonstrate that SELFI enables early diagnosis of PDAC, as indicated by a receiver operating characteristic curve and a larger area under the curve compared to the enzyme-linked immunosorbent assay. SELFI's effective diagnostic features can enhance the timely identification of PDAC and may also serve in the early diagnosis of a range of other diseases.

BACKGROUND: NUT carcinoma is a rare but highly lethal solid tumor without an effective standard of care. NUT carcinoma is caused by bromodomain-containing NUTM1 fusion oncogenes, most commonly BRD4::NUTM1. BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called "megadomains" with the overexpression of corresponding oncogenes, including MYC. We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable.

METHODS: We integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single-labeled and double-labeled peptide standards, and gain/loss-of-function genetic experiments on a panel of cell lines (N=5), a patient-derived xenograft, a tissue microarray (N=77), and patient samples from the Tempus AI Sequencing Database harboring evidence of NUTM1 fusions (N=165). We created an αPRAME425 T-cell receptor (TCR) × SP34 αCD3 bispecific molecule modeled after brenetafusp, an αPRAME425 TCR bispecific T-cell engager, as well as αPRAME425 TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells in vitro.

RESULTS: We identified PRAME as the most commonly expressed cancer/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions (BRD4::NUTM1, BRD3::NUTM1, and NSD3::NUTM1). Additionally, 56% (43/77) of NUT carcinoma tissue microarray samples stained positive for PRAME. BRD4::NUTM1 expression in HEK 293T cells enhanced PRAME levels and BRD4::NUTM1 knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived human leukocyte antigen (HLA) ligands (N=9) than all other cancer/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01/SLLQHLIGL (PRAME425) epitope in 100% (4/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (>0.01 fM) than HLA-A*02:01/RLDQLLRHV (PRAME312) or HLA-A*02:01/YLHARLREL (PRAME462). The αPRAME425 TCR × SP34 αCD3 bispecific molecule and αPRAME425 TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against PRAME+ NUT carcinoma cells.

CONCLUSIONS: PRAME is highly and frequently expressed in NUT carcinoma, and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrants clinical trials testing PRAME-targeted immunotherapies in this neglected patient population.

BACKGROUND: Oral anticoagulation (OAC) reduces stroke in patients with atrial fibrillation (AF), but increases bleeding.

OBJECTIVES: This study aimed to evaluate an updated version of the Age, Biomarkers, and Clinical history of bleeding in AF (ABC-AF)-bleeding score (2.0) including consideration of OAC type (direct oral anticoagulant [DOAC] or warfarin) and compare its performance with other bleeding risk scores in 25 962 patients from the COMBINE AF cohort.

METHODS: The COMBINE AF biomarker cohort contains individual participant data from patients with AF enrolled in 3 pivotal randomized trials comparing DOACs with warfarin. The biomarkers in the ABC-AF-bleeding score (growth differentiation factor 15, hemoglobin, and troponin-T) were analyzed in baseline samples. The biomarker-based ABC-AF-bleeding score was updated (version 2.0) by incorporating OAC type into the model (DOAC or warfarin). Discrimination was assessed by Harrell C-index and compared with clinically based bleeding scores; HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol), DOAC, and ORBIT (Older age, Reduced haemoglobin/haematocrit or history of anaemia, Bleeding history, Insufficient renal function, Treatment with antiplatelet agents).

RESULTS: During follow-up, 1321 patients (5.1%) had an International Society on Thrombosis and Haemostasis major bleeding event, including 480 gastrointestinal, and 248 intracranial hemorrhages. The ABC-AF-bleeding 2.0 risk score showed better discrimination and calibration than the original version and provided superior discrimination than clinical risk scores for all outcomes. The ABC-AF-bleeding score 2.0 C-indices for major bleeding were 0.69 (95% CI, 0.68-0.71); gastrointestinal bleeding, 0.72 (95% CI, 0.69-0.74); and intracranial bleeding, 0.66 (95% CI, 0.63-0.70). The ABC-AF-bleeding score 2.0 also provided consistent superior discrimination in clinically relevant subgroups.

CONCLUSION: The updated ABC-AF-bleeding score 2.0 provided better discrimination and calibration for the risk of major bleeding than clinical risk scores, which was consistent across multiple subgroups. These findings support the utility of the ABC-AF-bleeding score for advancing precision medicine in AF.

BACKGROUND: International guidelines regarding the resumption of postoperative intake of liquids are limited. Surgical patients are subjected to unnecessarily prolonged fasting times after surgery, which can lead to increased postoperative complications. Research has shown that a shorter fasting duration can enhance recovery, improve rehabilitation, and reduce the psychological stress associated with major surgeries in these patients. Given these potential benefits, we performed this meta-analysis that aims to explore how the duration of postoperative liquid fasting affects the length of hospital stay.

METHODS: We systematically searched the literature for papers published in English between 1 January 2010 and 6 January 2023. Meta-analyses were performed using R (version 4.0.2). When means and standard deviations were lacking, these were derived from medians and interquartile ranges if available. For the length of hospital stay (a continuous variable), the standardised mean difference (SMD) and 95% confidence intervals were calculated to summarise the data. We used a random-effects model when high heterogeneity was observed (I2 > 50%). To account for potential causes of heterogeneity, we performed subgroup analyses according to the type of papers (dividing papers into randomised controlled trials and observational studies; and papers with or without mean derivation from medians). Risk of publication bias was checked by drawing funnel plots.

RESULTS: A total of nine studies were included. The definition of 'early feeding' varied according to the type of procedures included across studies. Shorter postoperative fasting with earlier postoperative intake of liquids was associated with a decrease in the length of hospital stay with a mean difference of 0.9 day (p < 0.05). Results remained similar after sensitivity analysis.

CONCLUSIONS: Shorter postoperative fasting with earlier postoperative intake of liquids is associated with a decreased length of hospital stay. Future research is needed to explore the relation between postoperative fasting times and length of hospital stay according to the types of surgeries.

EDITORIAL COMMENT: This systematic review confirms that successful early postoperative intake of liquids is associated with post-operative benefit defined as shorter hospital stay. This was shown in the selected non-interventional studies as well as the trial results, where all the individual study findings for the chosen outcome were in the same direction.

OBJECTIVE: To investigate the association, if any, between conception through assisted reproductive technology (ART) and depression or anxiety in pregnancy.

DESIGN: Secondary analysis of the prospective nulliparous pregnancy outcomes study: monitoring mothers-to-be (nuMoM2b).

SUBJECTS: Nulliparous women with singleton pregnancies EXPOSURE: Patients who conceived through ART (n = 366) were compared with those who conceived naturally (n = 8,922).

MAIN OUTCOME MEASURES: Maternal depressive and anxiety symptoms as assessed by the Edinburgh Postnatal Depression Scale (EPDS) and the Perceived Stress Scale (PSS) at the first and third trimesters and the State Trait Anxiety Inventory (STAI) at the first trimester.

RESULTS: The ART group had significantly lower EPDS and PSS scores compared with the non-ART group in the first and third trimesters. In unadjusted analysis, patients who conceived with ART were less likely to experience significant depressive symptoms, with EPDS ≥10 rates of 8.2% vs. 18.3% in the first trimester and 8.6% vs. 16.5% in the third trimester for ART and non-ART groups, respectively. High perceived stress (PSS 27-40) was also less common among ART patients, occurring in 0.5% vs. 3.7% in the first trimester and 0.6% vs. 2.4% in the third trimester. However, after adjustments, the ART group had similar significant depression rates both in the first and third trimesters compared with the non-ART group. Likewise, in adjusted analysis, high perceived stress rates were similar between the 2 groups in both trimesters. There were no significant differences in the STAI questionnaire responses in the unadjusted or adjusted analysis.

CONCLUSION: Patients who conceive with ART display similar depression symptoms during the first and third trimesters of pregnancy compared with those with unassisted conception. Additionally, perceived stress is comparable in both the first and third trimesters between the 2 groups.

BACKGROUND: The Best Endovascular vs Surgical Therapy in Patients with Chronic Limb-Threatening Ischemia (CLTI) (BEST-CLI) trial compared surgical bypass and endovascular treatment in patients with CLTI. Although center-level variation in vascular surgery outcomes is well-documented, its impact within BEST-CLI has not been explored. Moreover, traditional quality metrics often fail to adequately discriminate center-level performance. This study introduces cumulative, probability-based quality metrics-similar to those employed in professional sports (earned outcomes [EO] and wins above average [WAA])-to evaluate center-level performance in both surgical and endovascular treatment of CLTI. We hypothesized that high performance in both modalities conferred the best overall outcomes among centers.

METHODS: Participating BEST-CLI centers were evaluated by composite major adverse limb events (MALE) or death, for all patients treated at a given site (bypass and endovascular, all BEST-CLI cohorts). WAA was calculated as a risk-adjusted, volume-sensitive measure derived from MALE/death using EO methods. Risk adjustment accounted for patient-level differences using a Cox proportional hazards model, excluding patients with incomplete data. Centers were ranked and divided into WAA quartiles from bottom (Q1) to top (Q4). Patient-level demographics and outcomes were compared across quartiles. Centers were further categorized based on WAA performance: above average (WAA >0) or below average (WAA <0) in bypass, endovascular therapy, or both.

RESULTS: Analyses included 1440 patients (79% of randomized patients) across 146 centers. At 2 years, unadjusted MALE/death rates varied significantly by quartile (bottom Q1, 58%; Q2, 43%; Q3, 33%; top Q4: 30%; P < .001). Centers were evenly distributed based on WAA: both modalities above average (27%), bypass above average only (27%), endovascular above average only (21%), and both below average (25%). Among top centers (Q4), 84% achieved above average outcomes in both modalities, whereas 62% of bottom centers (Q1) were below average in both. Centers excelling in only one modality constituted 16% of top centers (3% bypass above average only, 14% endovascular above average only) and 38% of bottom centers (27% bypass above average only, 11% endovascular above average only).

CONCLUSIONS: MALE/death varied considerably among BEST-CLI centers, with a difference of approximately 30% seen at 2 years between the bottom and top quartiles. Top performing centers consistently achieved above-average outcomes in both bypass and endovascular treatment. Conversely, centers exceling in only one modality were less likely to be top performers. These findings suggest that optimal CLTI care demands proficiency in both bypass and endovascular treatment and highlights the need for quality metrics that better differentiate center-level performance.