Daily Papers

Differential diagnosis is crucial for medicine as it helps healthcare providers systematically distinguish between conditions that share similar symptoms. This study assesses the impact of lab test results on differential diagnoses (DDx) made by large language models (LLMs). Clinical vignettes from 50 case reports from PubMed Central were created incorporating patient demographics, symptoms, and lab results. Five LLMs GPT-4, GPT-3.5, Llama-2-70b, Claude-2, and Mixtral-8x7B were tested to generate Top 10, Top 5, and Top 1 DDx with and without lab data. A comprehensive evaluation involving GPT-4, a knowledge graph, and clinicians was conducted. GPT-4 performed best, achieving 55% accuracy for Top 1 diagnoses and 60% for Top 10 with lab data, with lenient accuracy up to 80%. Lab results significantly improved accuracy, with GPT-4 and Mixtral excelling, though exact match rates were low. Lab tests, including liver function, metabolic/toxicology panels, and serology/immune tests, were generally interpreted correctly by LLMs for differential diagnosis.

Convolutional neural networks (CNNs) are the current state-of-the-art meta-algorithm for volumetric segmentation of medical data, for example, to localize COVID-19 infected tissue on computer tomography scans or the detection of tumour volumes in magnetic resonance imaging. A key limitation of 3D CNNs on voxelised data is that the memory consumption grows cubically with the training data resolution. Occupancy networks (O-Nets) are an alternative for which the data is represented continuously in a function space and 3D shapes are learned as a continuous decision boundary. While O-Nets are significantly more memory efficient than 3D CNNs, they are limited to simple shapes, are relatively slow at inference, and have not yet been adapted for 3D semantic segmentation of medical data. Here, we propose Occupancy Networks for Semantic Segmentation (OSS-Nets) to accurately and memory-efficiently segment 3D medical data. We build upon the original O-Net with modifications for increased expressiveness leading to improved segmentation performance comparable to 3D CNNs, as well as modifications for faster inference. We leverage local observations to represent complex shapes and prior encoder predictions to expedite inference. We showcase OSS-Net's performance on 3D brain tumour and liver segmentation against a function space baseline (O-Net), a performance baseline (3D residual U-Net), and an efficiency baseline (2D residual U-Net). OSS-Net yields segmentation results similar to the performance baseline and superior to the function space and efficiency baselines. In terms of memory efficiency, OSS-Net consumes comparable amounts of memory as the function space baseline, somewhat more memory than the efficiency baseline and significantly less than the performance baseline. As such, OSS-Net enables memory-efficient and accurate 3D semantic segmentation that can scale to high resolutions.

Most human proteins remain undrugged, over 96% of human proteins remain unexploited by approved therapeutics. While structure-based virtual screening promises to expand the druggable proteome, existing methods lack atomic-level precision and fail to predict binding fitness, limiting translational impact. We present AuroBind, a scalable virtual screening framework that fine-tunes a custom atomic-level structural model on million-scale chemogenomic data. AuroBind integrates direct preference optimization, self-distillation from high-confidence complexes, and a teacher-student acceleration strategy to jointly predict ligand-bound structures and binding fitness. The proposed models outperform state-of-the-art models on structural and functional benchmarks while enabling 100,000-fold faster screening across ultra-large compound libraries. In a prospective screen across ten disease-relevant targets, AuroBind achieved experimental hit rates of 7-69%, with top compounds reaching sub-nanomolar to picomolar potency. For the orphan GPCRs GPR151 and GPR160, AuroBind identified both agonists and antagonists with success rates of 16-30%, and functional assays confirmed GPR160 modulation in liver and prostate cancer models. AuroBind offers a generalizable framework for structure-function learning and high-throughput molecular screening, bridging the gap between structure prediction and therapeutic discovery.

Hepato-pancreato-biliary (HPB) disorders represent a global public health challenge due to their high morbidity and mortality. Although large language models (LLMs) have shown promising performance in general medical question-answering tasks, the current evaluation benchmarks are mostly derived from standardized examinations or manually designed questions, lacking HPB coverage and clinical cases. To address these issues, we systematically eatablish an HPB disease evaluation benchmark comprising 3,535 closed-ended multiple-choice questions and 337 open-ended real diagnosis cases, which encompasses all the 33 main categories and 465 subcategories of HPB diseases defined in the International Statistical Classification of Diseases, 10th Revision (ICD-10). The multiple-choice questions are curated from public datasets and synthesized data, and the clinical cases are collected from prestigious medical journals, case-sharing platforms, and collaborating hospitals. By evalauting commercial and open-source general and medical LLMs on our established benchmark, namely ClinBench-HBP, we find that while commercial LLMs perform competently on medical exam questions, they exhibit substantial performance degradation on HPB diagnosis tasks, especially on complex, inpatient clinical cases. Those medical LLMs also show limited generalizability to HPB diseases. Our results reveal the critical limitations of current LLMs in the domain of HPB diseases, underscoring the imperative need for future medical LLMs to handle real, complex clinical diagnostics rather than simple medical exam questions. The benchmark will be released at https://clinbench-hpb.github.io.

The structure-function relationship is at the heart of biology and major protein deformations are correlated to specific functions. In the case of heme proteins, doming is associated with the respiratory function in hemoglobin and myoglobin, while ruffling has been correlated with electron transfer processes, such as in the case of Cytochrome c (Cyt c). The latter has indeed evolved to become an important electron transfer protein in humans. In its ferrous form, it undergoes ligand release and doming upon photoexcitation, but its ferric form does not release the distal ligand, while the return to the ground state has been attributed to thermal relaxation. Here, by combining femtosecond Fe K-edge X-ray absorption near-edge structure (XANES) studies and femtosecond Fe Kalpha and Kbeta X-ray emission spectroscopy (XES), we demonstrate that the photocycle of ferric Cyt c is entirely due to a cascade among excited spin states of the Iron ion, causing the ferric heme to undergo doming, which we identify for the first time. We also argue that this pattern is common to all ferric haems, raising the question of the biological relevance of doming in such proteins.

Model-based reconstruction employing the time separation technique (TST) was found to improve dynamic perfusion imaging of the liver using C-arm cone-beam computed tomography (CBCT). To apply TST using prior knowledge extracted from CT perfusion data, the liver should be accurately segmented from the CT scans. Reconstructions of primary and model-based CBCT data need to be segmented for proper visualisation and interpretation of perfusion maps. This research proposes Turbolift learning, which trains a modified version of the multi-scale Attention UNet on different liver segmentation tasks serially, following the order of the trainings CT, CBCT, CBCT TST - making the previous trainings act as pre-training stages for the subsequent ones - addressing the problem of limited number of datasets for training. For the final task of liver segmentation from CBCT TST, the proposed method achieved an overall Dice scores of 0.874pm0.031 and 0.905pm0.007 in 6-fold and 4-fold cross-validation experiments, respectively - securing statistically significant improvements over the model, which was trained only for that task. Experiments revealed that Turbolift not only improves the overall performance of the model but also makes it robust against artefacts originating from the embolisation materials and truncation artefacts. Additionally, in-depth analyses confirmed the order of the segmentation tasks. This paper shows the potential of segmenting the liver from CT, CBCT, and CBCT TST, learning from the available limited training data, which can possibly be used in the future for the visualisation and evaluation of the perfusion maps for the treatment evaluation of liver diseases.

Perfusion imaging is a valuable tool for diagnosing and treatment planning for liver tumours. The time separation technique (TST) has been successfully used for modelling C-arm cone-beam computed tomography (CBCT) perfusion data. The reconstruction can be accompanied by the segmentation of the liver - for better visualisation and for generating comprehensive perfusion maps. Recently introduced Turbolift learning has been seen to perform well while working with TST reconstructions, but has not been explored for the time-resolved volumes (TRV) estimated out of TST reconstructions. The segmentation of the TRVs can be useful for tracking the movement of the liver over time. This research explores this possibility by training the multi-scale attention UNet of Turbolift learning at its third stage on the TRVs and shows the robustness of Turbolift learning since it can even work efficiently with the TRVs, resulting in a Dice score of 0.864pm0.004.

Purpose: To evaluate the performance of an automated deep learning method in detecting ascites and subsequently quantifying its volume in patients with liver cirrhosis and ovarian cancer. Materials and Methods: This retrospective study included contrast-enhanced and non-contrast abdominal-pelvic CT scans of patients with cirrhotic ascites and patients with ovarian cancer from two institutions, National Institutes of Health (NIH) and University of Wisconsin (UofW). The model, trained on The Cancer Genome Atlas Ovarian Cancer dataset (mean age, 60 years +/- 11 [s.d.]; 143 female), was tested on two internal (NIH-LC and NIH-OV) and one external dataset (UofW-LC). Its performance was measured by the Dice coefficient, standard deviations, and 95% confidence intervals, focusing on ascites volume in the peritoneal cavity. Results: On NIH-LC (25 patients; mean age, 59 years +/- 14 [s.d.]; 14 male) and NIH-OV (166 patients; mean age, 65 years +/- 9 [s.d.]; all female), the model achieved Dice scores of 0.855 +/- 0.061 (CI: 0.831-0.878) and 0.826 +/- 0.153 (CI: 0.764-0.887), with median volume estimation errors of 19.6% (IQR: 13.2-29.0) and 5.3% (IQR: 2.4-9.7) respectively. On UofW-LC (124 patients; mean age, 46 years +/- 12 [s.d.]; 73 female), the model had a Dice score of 0.830 +/- 0.107 (CI: 0.798-0.863) and median volume estimation error of 9.7% (IQR: 4.5-15.1). The model showed strong agreement with expert assessments, with r^2 values of 0.79, 0.98, and 0.97 across the test sets. Conclusion: The proposed deep learning method performed well in segmenting and quantifying the volume of ascites in concordance with expert radiologist assessments.

Automatic segmentation of the liver and hepatic lesions is an important step towards deriving quantitative biomarkers for accurate clinical diagnosis and computer-aided decision support systems. This paper presents a method to automatically segment liver and lesions in CT and MRI abdomen images using cascaded fully convolutional neural networks (CFCNs) enabling the segmentation of a large-scale medical trial or quantitative image analysis. We train and cascade two FCNs for a combined segmentation of the liver and its lesions. In the first step, we train a FCN to segment the liver as ROI input for a second FCN. The second FCN solely segments lesions within the predicted liver ROIs of step 1. CFCN models were trained on an abdominal CT dataset comprising 100 hepatic tumor volumes. Validations on further datasets show that CFCN-based semantic liver and lesion segmentation achieves Dice scores over 94% for liver with computation times below 100s per volume. We further experimentally demonstrate the robustness of the proposed method on an 38 MRI liver tumor volumes and the public 3DIRCAD dataset.