Citations

Abstract Spatial transcriptomics links gene expression to tissue architecture, providing a mechanistic view of cellular organization. Yet existing datasets cover few donors and miss the complexity of human disease. Experimental costs remain prohibitive, and large-scale profiling is impractically slow for population-level studies. Accurate computational methods are urgently needed. Predicting gene expression from standard histology, however, remains an open problem, as current approaches transfer poorly to unseen cohorts and diseases. Here, we present Phoenix, a (latent) flow matching generative model that infers pan-cancer spatially resolved single-cell gene expression with high accuracy. Phoenix analyzes treatment response in silico: Applied to 763 head and neck cancer patients, it identified three new spatial biomarkers that we validated across two cancers (breast cancer, n = 84; ovarian cancer, n = 157) and treatment regimens (platinum, trastuzumab). Phoenix generalizes beyond carcinomas: In a large sarcoma cohort (802 tissue microarray cores), it accurately predicted cell-type-specific signatures in held-out samples and captured chemotherapy-induced immune remodeling. Phoenix also extends across species: In a mouse model, it accurately predicted the expression of pancreatic cancer lineage markers and the mutant mKras^G12D allele in silico. In total, we evaluated Phoenix on over 10,000 patients. Our results establish virtual spatial transcriptomics as a scalable framework for studying tissue organization, therapeutic response, and disease mechanisms.

The diagnosis of coccidioidomycosis is often achieved serologically by the detection of antibodies against fungal antigens. While several serologic tests are available for coccidioidomycosis, all of them are performed in a laboratory setting causing delays in diagnosis and therapeutic intervention. Point-of-care testing offers the ability to provide a shorter time to result by avoiding specimen send-out, minimizing processing steps, and employing expeditious immunochemical techniques. A preliminary trial of a rapid anti-coccidioidal antibody lateral flow assay (LFA) using fingerstick blood was performed on 22 patients with coccidioidomycosis at the point of care during outpatient clinic visits. Patients were tested longitudinally over the course of one year. An LFA reader was implemented to provide an objective result by quantifying the intensity of the test line band. There was close qualitative concordance observed between positive LFA results with send-out immunodiffusion (89.5%) and complement fixation (78.4%) standard of care clinical laboratory assays. Additionally, the relationship between LFA test line density values and traditional complement fixation antibody titers was assessed.

Abstract Importance Decline in olfactory function may be used as a predictor of cognitive decline, to enhance early detection models, improve risk stratification, and enable early intervention. Objective To assess the longitudinal association between olfactory decline, cognitive decline, and postmortem neuropathology. Design, setting and participants Retrospective longitudinal analysis with clinicopathological correlations of a prospective population-based cohort study using data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and its Brain and Body Donation Program. Participants included cognitively unimpaired individuals without parkinsonism that converted to mild cognitive impairment (MCI) and/or dementia or remained cognitively stable. Main Outcomes and Measures longitudinal change in olfaction, neuropsychiatric symptoms, motor function and memory, conversion to MCI/dementia, postmortem neuropathology Results Over a mean follow-up period of 7.7 ± 5.4 years, out of 922 participants who were cognitively unimpaired at the first cognitive conference, 643 remained cognitively unimpaired, 279 converted to MCI, and 82 developed dementia. Of these, 633 individuals had at least 2 olfactory tests. Converters showed reduced olfactory function (t=-12.6, p <0.0001), faster progression in neuropsychiatric symptom burden (t=3.42, p < 0.001), and faster decline in memory (t= -7.33, p <0.0001) prior to conversion while no significant differences were observed in motor scores between converters and non-converters. Using ROC analysis, olfactory decline, increased neuropsychiatric symptom burden, as well as motor and memory decline predicted conversion to MCI with a consistent accuracy of ∼ 70% up to 5 years before conversion, while UPSIT alone had an accuracy of ∼ 60%. Longitudinal decline in olfaction was associated with a higher burden of a-synuclein (t= -8.21, p <0.0005), tau tangle (t= -2.66, p < 0.01) and amyloid plaque burden (t= -2.85, p < 0.005) and a faster decline over time was associated with a higher burden of tau (t=5.66, p<0.0001). Conclusions and Relevance A reduction in olfactory identification ability is observed up to a decade prior to conversion to MCI and is associated with underlying burden of neuropathology markers, underscoring the value of incorporating olfactory testing in cognitively unimpaired individuals to identify those at-risk of future cognitive decline.

Abstract Background Presacral tumours are rare and heterogeneous lesions arising within a complex anatomical space, resulting in variability in diagnosis and management. Increasing incidental detection and evolving surgical and oncological strategies have highlighted the need for contemporary guidance. The aim of this study was to establish an international expert consensus on the optimal diagnosis and management of presacral tumours. Methods An international panel of colorectal surgeons from high-volume units was convened. Evidence- and practice-based statements were developed after domain-based literature reviews and refined through five online and two in-person meetings. Consensus was achieved using a modified Delphi process with anonymous voting. Results In total, 16 colorectal surgeons participated in the study. Ten domains were identified resulting in the development of 22 statements based on expert opinion and retrospective studies. After two rounds, unanimous (100%) agreement was achieved for all statements. High-resolution MRI with structured synoptic reporting is endorsed as central to risk stratification. Selective image-guided transperineal or parasacral biopsy is recommended for high-risk lesions where histology would alter management. Complete surgical resection is defined as the operative goal, with approach tailored to tumour biology and anatomy; minimally invasive surgery is considered appropriate in selected cases. Non-operative surveillance is supported for carefully selected asymptomatic, low-risk cystic lesions. Postoperative surveillance is recommended in a risk-adapted manner according to histopathology and margin status. Conclusion This international consensus provides a pragmatic, risk-stratified framework for the multidisciplinary diagnosis and management of presacral tumours. These recommendations aim to reduce practice variation, support decision-making in specialized centres, and inform future prospective collaborative research.

Abstract Parkinson’s disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.

BACKGROUND: Radiofrequency (RF) ablation of premature ventricular complexes (PVCs) originating from the left ventricular summit may be unsuccessful, highlighting the need for alternative approaches. We aimed to assess the efficacy and safety of a novel dual-modality focal catheter in treating left ventricular summit PVCs in patients who had failed previous RF ablation. METHODS: Patients were prospectively enrolled and underwent a redo ablation procedure using an irrigated, contact-force sensing, dual-modality focal catheter (TactiFlex Duo, Abbott) under compassionate use indication. The ablation strategy, including the choice of energy modality (monopolar pulsed field [PF], RF, or both), was left to the operator’s discretion. Safety assessments included serial biomarkers, renal function, and CMR within 36 hours. Efficacy was defined as ≥80% reduction in PVC burden with symptom resolution at 3-month follow-up. RESULTS: Six consecutive patients (4 men; mean age, 53.8±15 years) with symptomatic left ventricular summit PVCs and a prior failed RF ablation (range, 1–2) were prospectively enrolled. All PVCs had an inferior axis, with a left bundle V1 morphology observed in 4 of 6 cases (mean burden, 30.1±5.3%). Acute suppression of PVCs was achieved in all cases. Acute suppression with a single PF application in the great cardiac vein-anterior interventricular vein occurred in 2 patients, while 3 patients required additional RF, PF, or combined RF+PF applications at adjacent sites. One patient with an inaccessible great cardiac vein-anterior interventricular vein was successfully treated in the left ventricular outflow tract with RF+PF application. Transient, reversible left anterior descending vasospasm was observed during PF delivery in 2 of 5 cases that underwent PF application adjacent to a coronary artery, despite pretreatment with intracoronary nitroglycerin without ECG or hemodynamic sequelae. All patients had durable suppression of PVCs at follow-up. CONCLUSIONS: In its first human application, dual-modality ablation was feasible and effective for refractory left ventricular summit PVCs. Transient coronary vasospasm occurred, though it was reversible and without acute clinical consequences.

ABSTRACT Background Clinical T 2 ‐weighted (T2W) MRI of prostate cancer (PCa) usually implements a 2D fast‐spin‐echo (FSE) sequence, but understanding the echo‐time‐dependent contrast behavior is not straightforward due to the complicated FSE signal evolution. Consequently, consensus‐based recommendations on the optimal effective echo time (TE eff ) to maximize contrast are lacking. Purpose To investigate the effect of TE eff on PCa lesion contrast in prostate T2W MRI. Study Type Phantom and in vivo prospective study. Subjects A standard MRI phantom and 53 prostate cancer patients (29 for image evaluation and 24 for quantitative lesion analysis). Field Strength and Sequence Multi‐slice T2W FSE sequence at 3 T acquired at multiple TE eff values. Assessment Three readers (13, 25, and 27 years' experience) evaluated TE eff = 100 ms versus 150 ms on diagnostic quality and reader preference. The effective T 2 relaxation rates ( T 2,eff ) were measured using FSE sequences in the phantom and used to predict the optimal TE eff maximizing T2W contrasts. From multi‐TE eff scans of subjects with suspected PCa, T 2,eff values of PCa lesions and healthy tissue were measured and used to calculate the optimal TE eff maximizing the lesion contrast. In vivo contrast metrics were measured as a function of TE eff . Statistical Tests Wilcoxon test of reader scores, with p < 0.05 defining statistical significance. Results No statistically significant difference was found in diagnostic quality between TE eff = 150 ms and 100 ms images, but all three readers significantly favored TE eff = 150 ms. Phantom experiments demonstrated that TE eff ‐dependent FSE signal progression can be characterized by T 2,eff values typically 40% longer than actual T 2 values, allowing accurate prediction of optimal TE eff within 2%–5%. Applied to PCa imaging, in vivo measurements indicated that effective T 2 relaxation times of the prostate are on average 1.5× longer than published T 2 values. Data Conclusion The benefits of TE eff = 150 ms versus 100 ms in prostate T2W FSE were supported by reader preference, phantom experiments, in vivo measurements, and analytic optimizations. Evidence Level 2. Technical Efficacy 2.