Publications by Year: 2025

Liver Imaging Reporting and Data System (LI-RADS) category 3 (LR-3) observations remain indeterminate and often result in repeated follow-up or biopsy. Prostate-specific membrane antigen (PSMA) is overexpressed in hepatocellular carcinoma (HCC) neovasculature and may serve as a useful imaging biomarker. This study aimed to evaluate whether [68Ga]Ga-PSMA-11 PET/MRI improved characterization of LR-3 observations in patients with cirrhosis compared with MRI alone. Methods: In this prospective study, conducted between March 2022 and June 2024, 19 patients with cirrhosis and 54 LR-3 observations identified on prior MRI underwent [68Ga]Ga-PSMA-11 PET/MRI. An observation was classified as HCC if it demonstrated focal 68Ga-PSMA uptake greater than background liver combined with at least 1 LI-RADS major or ancillary feature. The reference standard was histopathology or a follow-up MRI within 12 mo. Diagnostic metrics were calculated. Univariable logistic regression and decision tree analysis were performed to identify imaging predictors of malignancy. Results: Of the 54 LR-3 observations, 13 (24%) were confirmed as HCC and 41 (76%) as benign. [68Ga]Ga-PSMA-11 PET/MRI correctly identified 12 of 13 HCCs (sensitivity, 92%; 95% CI, 66.7-99.6) and 39 of 41 benign observations (specificity, 95%; 95% CI, 81.9-99.3). Overall diagnostic accuracy was 94%, with a positive predictive value of 86% and negative predictive value of 97%. Diagnostic performance was significantly better than MRI alone (McNemar test, P < 0.001). [68Ga]Ga-PSMA-11 uptake was the only significant imaging predictor of malignancy on univariable analysis (odds ratio, 5.7; P = 0.017). Decision tree analysis identified [68Ga]Ga-PSMA-11 uptake, observation size, and hepatobiliary phase hypointensity as principal discriminators. Conclusion: [68Ga]Ga-PSMA-11 PET/MRI demonstrates high diagnostic accuracy in differentiating malignant from benign LR-3 liver observations in patients with cirrhosis. This technique may reduce unnecessary follow-up imaging and biopsy. These results support further validation of [68Ga]Ga-PSMA-11 PET/MRI as a promising imaging approach for indeterminate liver observations.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapies are highly efficacious for several different hematologic cancers. However, for most CAR T targets it is observed that low surface antigen density on tumors can significantly reduce therapeutic efficacy. In this study, we explore this dynamic in the context of CD72, a surface antigen we recently found as a promising target for refractory B-cell cancers, but for which CD72 low antigen density can lead to therapeutic resistance in preclinical models.

METHODS: Primary samples were accessed via institutional review board-approved protocols. Affinity-matured and humanized nanobody clones were previously described in Temple et al. (2023). CAR T cells were generated via lentiviral transduction. In vitro cytotoxicity assays were performed using luciferase-labeled cell lines. In vivo studies were performed using cell line-derived or patient-derived xenografts implanted in NOD scid gamma mice.

RESULTS: We first confirmed ubiquitous CD72 expression across a range of primary B-cell non-Hodgkin lymphomas. We further found that after resistance to CD19-directed therapies, across both B-cell acute lymphoblastic leukemia (B-ALL) models and primary tumor samples, surface CD72 expression was largely preserved while CD22 expression was significantly diminished. Affinity maturation of a nanobody targeting CD72, when incorporated into CAR T cells, led to more effective elimination in vitro of isogenic models of CD72 low-expressing tumors. These results suggested that nanobody-based CAR T cells (nanoCARs) may exhibit a similar relationship between binder affinity, antigen expression, and efficacy as previously demonstrated only for single chain variable fragment-based CAR T cells. Surprisingly, however, this significantly improved in vitro efficacy only translated to modest in vivo survival benefit. As a parallel strategy to enhance CAR T function, we found that the small molecule bryostatin could also significantly increase CD72 surface antigen density on B-cell malignancy models. Structural modeling and biochemical analysis identified critical residues improving CD72 antigen recognition of our lead affinity-matured nanobody.

CONCLUSIONS: Together, these findings support affinity-matured CD72 nanoCARs as a potential immunotherapy product for CD19-refractory B-cell cancers. Our results also suggest that for B-ALL in particular, CD72 may be a preferable second-line immunotherapy target over CD22.

INTRODUCTION: Visual Patient Predictive (VPP) is an AI-based extension of the Visual Patient Avatar (VPA) that integrates deep learning models to predict upcoming vital sign deviations and display them as dashed visual elements. By explicitly showing anticipated changes, the system aims to support level 3 situation awareness-the projection of future patient states. This multicentre simulation study will evaluate whether predictive algorithms and visualisations integrated into the VPA (resulting in VPP) improve clinicians' ability to anticipate critical vital sign changes compared with conventional number-based and waveform-based monitoring and examine its effects on decision-making, confidence, workload and user acceptance.

METHODS AND ANALYSIS: This investigator-initiated, randomised, within-subjects crossover, computer-based simulation trial will be conducted at five academic centres in Switzerland, Germany and the United States. Medical professionals from anaesthesiology departments will complete scenario-based prediction tasks using both VPP (as the index test) and conventional monitoring (as the reference standard) in randomised order, with the same participant evaluating both modalities and the identical underlying clinical scenario used in each condition, following video-based training and a learnability test. The primary outcome is recall (true positive rate) of vital sign deviation predictions. Secondary outcomes include average lead time, precision, prediction confidence, number and correctness of proposed interventions, perceived workload (NASA-TLX) and qualitative usability feedback. Quantitative data will be analysed using a logistic generalised linear mixed model with random intercepts for centre and participant, and a random slope for the intervention effect. Qualitative interviews will undergo thematic analysis.

ETHICS AND DISSEMINATION: The leading ethics committee (Zurich, Switzerland; BASEC-Req-2023-00465) reviewed and approved the study protocol. Ethics committees at the other participating centres have obtained their respective approvals or waivers. Bonn: 2025-144-BO, Boston: 2025P000501, Heidelberg: S-376/2025, Munich: 2025-357 W-CB. As this simulation study involves only healthcare professionals performing prediction tasks based on simulated vital sign scenarios-without collection of patient data or any medically relevant personal data-it does not constitute human subjects research under applicable regulations. Study results will be disseminated through peer-reviewed publications and presentations at scientific conferences.

BACKGROUND: Right heart catheterisation (RHC) with pulmonary capillary wedge pressure (PCWP) assessment is the reference standard for diagnosis of heart failure with preserved ejection fraction (HFpEF), remains however largely underused. Different approaches for non-invasive PCWP calculation have been proposed. However, as left atrial strain (LA Es) and volume index (ESVi) emerge as a key-criteria in HFpEF, we sought to investigate them for PCWP calculation.

METHODS: The derivation population consisted of patients referred to RHC and cardiovascular magnetic resonance (CMR) imaging who were enrolled in a prospective monocentric registry. Patients were classified by RHC according to current guideline recommendations. The external validation population consisted of patients included in the HFpEF-Stress trial who underwent exercise-stress RHC and CMR with follow-up after 4 years for hospitalised cardiovascular events. Performance of strain-derived PCWP was compared to a published LA volume (LAV) and LV mass (LVM) derived method.

RESULTS: The derivation population consisted of n=209 patients, n=123 underwent exercise-stress RHC (n=55 without PH, n=72 pre-capillary, n=27 combined post- and pre-capillary pulmonary hypertension (CpcPH), n=15 isolated post-capillary pulmonary hypertension (IpcPH), n=34 exercise and n=6 unclassified PH). Linear regressions models identified the following formulae for functional PCWPrest 10.304-0.095*Es+0.098*ESVi and functional PCWPstress 24.666-0.251*Es+0.056*ESVi calculation. The validation population consisted of n=74 patients (n=15 without, n=5 pre-capillary, n=8 CpcPH, n=10 IpcPH and n=32 exercise PH with n=4 remaining unclassified). Functional PCWPrest (11.8) and RHC-derived PCWPrest (11mmHg) were statistically similar (p=0.285) and showed moderate correlation (r=0.53, p<0.001). Functional PCWPrest (AUC 0.80) and PCWPstress (AUC 0.85) accurately identified HFpEF patients, were superior to LAV/LVM based PCWP (AUC 0.67, p≤0.002) and showed prognostic implications (HR 1.37 (1.16-1.62) and 1.29 (1.14-1.46), p<0.001).

CONCLUSIONS: Functional PCWP may aide in the identification of post-capillary involvement in PH and HFpEF superiorly compared to morphology-derived PCWP and shows prognostic implications.

BACKGROUND: Understanding global patterns of adolescent noncombustible nicotine or tobacco product (NNTP) and combustible cigarette (CC) use is vital due to rising prevalence and long-term health risks, but comparative international analyses are lacking. Thus, we aimed to assess smoking prevalence and trends among adolescents in 57 countries and territories and to identify factors associated with NNTP and CC use.

METHODS: We utilized World Health Organization (WHO) Global Youth Tobacco Survey data to investigate adolescent NNTP and CC use prevalence and trends globally from 2014 to 2021. We conducted a meta-analysis using random-effects models to identify the summary effect of smoking prevalence in each country. Weighted linear regression was used to calculate weighted β coefficients with 95% confidence intervals (CIs). Each analysis was stratified by sex, World Bank income category, e-cigarette regulatory policy status, and WHO Framework Convention on Tobacco Control ratification status. Finally, a hierarchical Bayesian statistical model was employed to precisely predict the prevalence rates of both CC and NNTP use up to 2045.

RESULTS: Among the 57 countries with 173,658 adolescents, NNTP use exhibited a higher prevalence than CC use in 31 countries. Demographic groups exhibiting higher smoking prevalence included male adolescents (NNTP use: 10.78% [95% CI, 9.38 to 12.18]; CC use: 10.36% [9.03 to 11.69]), adolescents in high-income countries (NNTP use: 11.29% [8.62 to 13.95]; CC use: 10.48% [7.27 to 13.68]), and those in countries with less restrictive policies (NNTP use: 11.18% [7.32 to 15.04]; CC use: 11.44% [7.75 to 15.13]). Global NNTP use showed an overall increase from 2014 to 2021 (β, 0.73 [0.16 to 1.30]), with a particularly notable rise among male adolescents (β, 0.81 [0.05 to 1.57]). In 2044-2045, NNTP use is expected to remain relatively stable (10.61%), while CC use is projected to show a downward trend (1.05%).

CONCLUSION: Over half of the countries exhibited a higher prevalence of NNTP use than CC use. Global smoking prevalence varied across diverse factors. NNTP use among adolescents has increased, especially among male adolescents.

PURPOSE: Small fiber neuropathy (SFN) is a neurologic condition affecting small-diameter nerve fibers, including those innervating the ocular surface. In this study, we aim to assess the prevalence and characteristics of SFN symptoms in patients with dry eye disease (DED).

METHODS: This was a prospective study conducted at 2 academic eye centers. DED symptoms were assessed using the Ocular Surface Disease Index (OSDI) questionnaire, and adult patients with an OSDI score ≥13 and a clinical diagnosis of DED at Mass Eye and Ear and Beth Israel Deaconess Medical Center were included in the study. Ocular pain was assessed using the Ocular Pain Assessment Survey (OPAS). SFN symptoms were measured using validated Small-Fiber Symptom Survey (SSS) questionnaire, with scores ≥32.5 considered abnormal. DED signs including corneal fluorescein staining (CFS), tear breakup time (TBUT), tear production, and corneal sensitivity were assessed. Patients received standard DED treatments, and their responses were reassessed after 6 to 12 months.

RESULTS: Among 31 participants with DED (23-87 years, 80.6% female), 38.7% had abnormal SSS scores. SSS scores correlated with DED symptoms (r = 0.43 P = 0.017) and ocular pain (r = 0.62 P = 0.0003); correlated negatively with CFS (r = -0.42 P = 0.018); and did not correlate with TBUT, tear production, or corneal sensitivity. Despite standard treatments and stable clinical signs, most patients with severe SFN symptoms reported worsening dry eye symptoms in follow-up.

CONCLUSIONS: This study demonstrates that SFN symptoms were prevalent in DED population and positively correlated with ocular pain and dry eye symptoms and negatively with CFS. Patients with severe SFN symptoms reported less favorable responses to standard dry eye treatments.

The length of hospital stay following cardiac surgery remains a significant challenge. Enhanced recovery protocols, alongside the use of health applications, offer promising potential for safely and effectively reducing postoperative length of stay. The Registro Paulista de Cirurgia Cardiovascular III (REPLICCAR III) study, registered at Clinicaltrials.gov (NCT06786819), aimed to investigate the impact of an optimization application integrated within an optimized recovery-based protocol on postoperative hospitalization duration in patients undergoing Coronary Artery Bypass Graft Surgery (CABG) in the state of São Paulo.

Understanding the architectural principles that shape human brain networks is a major challenge for systems neuroscience. We hypothesize that the centrality of the different brain circuits in the human connectome is a product of their embryogenic age, such that early-born nodes should become stronger hubs than those born later. Using a human brain segmentation based on embryogenic age, we observed that nodes' structural centrality correlated with their embryogenic age, supporting our hypothesis. An opposite trend was found at functional level. The difference in embryonic age between nodes inversely correlated with the probability of existence of links and their weights. Brain transcriptomic analysis revealed strong associations between embryonic age, structure-function centrality, and the expression of genes related to nervous system development, synapse regulation and human neurological diseases. Our results highlight two key principles regarding the wiring of the human brain: older-get-richer rule, whereby earlier-born regions become network hubs, and a preferential-age-attachment rule, whereby regions preferentially connect to others with similar neurogenic timing.

For the MHC, MR1 and CD1 systems, antigen recognition involves contact of the membrane distal surfaces of both the αβ T cell receptor (TCR) and the antigen-presenting molecule. Whether other antigen display mechanisms by antigen-presenting molecules operate remains unknown. Here, we report mass spectrometry analyses of endogenous lipids captured by CD1c when bound to an autoreactive αβ TCR. CD1c binds twenty-six lipid species with bulky headgroups that cannot fit within the tight TCR-CD1c interface. We determined the crystal structures of CD1c presenting several gangliosides, revealing a general mechanism whereby two lipids, rather than one, are bound in the CD1c cleft. Bulky lipids are oriented sideways so that their polar headgroups protrude laterally through a side portal of the CD1c molecule - an evolutionarily conserved structural feature. The sideways-presented ganglioside headgroups do not hinder TCR binding and so represent a mechanism that allows autoreactive TCR recognition of CD1c. In addition, ex vivo studies showed that the sideways-presented gangliosides can also represent TCR recognition determinants. These findings reveal that CD1c simultaneously presents two lipid antigens from the top and side of its cleft, a general mechanism that differs markedly from other antigen-presenting molecules.