Towards Accurate Differential Diagnosis with Large Language Models

An accurate differential diagnosis (DDx) is a cornerstone of medical care, often reached through an iterative process of interpretation that combines clinical history, physical examination, investigations and procedures. Interactive interfaces powered by Large Language Models (LLMs) present new opportunities to both assist and automate aspects of this process. In this study, we introduce an LLM optimized for diagnostic reasoning, and evaluate its ability to generate a DDx alone or as an aid to clinicians. 20 clinicians evaluated 302 challenging, real-world medical cases sourced from the New England Journal of Medicine (NEJM) case reports. Each case report was read by two clinicians, who were randomized to one of two assistive conditions: either assistance from search engines and standard medical resources, or LLM assistance in addition to these tools. All clinicians provided a baseline, unassisted DDx prior to using the respective assistive tools. Our LLM for DDx exhibited standalone performance that exceeded that of unassisted clinicians (top-10 accuracy 59.1% vs 33.6%, [p = 0.04]). Comparing the two assisted study arms, the DDx quality score was higher for clinicians assisted by our LLM (top-10 accuracy 51.7%) compared to clinicians without its assistance (36.1%) (McNemar's Test: 45.7, p < 0.01) and clinicians with search (44.4%) (4.75, p = 0.03). Further, clinicians assisted by our LLM arrived at more comprehensive differential lists than those without its assistance. Our study suggests that our LLM for DDx has potential to improve clinicians' diagnostic reasoning and accuracy in challenging cases, meriting further real-world evaluation for its ability to empower physicians and widen patients' access to specialist-level expertise

Persistent organic pollutant burden, experimental POP exposure and tissue properties affect metabolic profiles of blubber from grey seal pups

Persistent organic pollutants (POPs) are toxic, ubiquitous, resist breakdown, bioaccumulate in living tissue and biomagnify in food webs. POPs can also alter energy balance in humans and wildlife. Marine mammals experience high POP concentrations, but consequences for their tissue metabolic characteristics are unknown. We used blubber explants from wild, grey seal (Halichoerus grypus) pups to examine impacts of intrinsic tissue POP burden and acute experimental POP exposure on adipose metabolic characteristics. Glucose use, lactate production and lipolytic rate differed between matched inner and outer blubber explants from the same individuals and between feeding and natural fasting. Glucose use decreased with blubber dioxin-like PCBs (DL-PCB) and increased with acute experimental POP exposure. Lactate production increased with DL-PCBs during feeding, but decreased with DL-PCBs during fasting. Lipolytic rate increased with blubber dichlorodiphenyltrichloroethane (DDT) and its metabolites (DDX) in fasting animals, but declined with DDX when animals were feeding. Our data show that POP burdens are high enough in seal pups to alter adipose function early in life, when fat deposition and mobilisation are vital. Such POP-induced alterations to adipose glucose use may significantly alter energy balance regulation in marine top predators with the potential for long term impacts on fitness and survival

Violaxanthin and diadinoxanthin de-epoxidation in various model lipid systems

The xanthophyll cycle is an important photoprotective process functioning in plants. One of its forms, the violaxanthin (Vx) cycle, involves interconversion between: Vx, antheraxanthin (Ax) and zeaxanthin (Zx). Another kind of the xanthophyll cycle is the diadinoxanthin (Ddx) cycle in which interconversion between Ddx and diatoxanthin (Dtx) occurs. In this study an information on molecular mechanism and regulation of these two types of the xanthophyll cycle is presented. The influence of lipids on the de-epoxidation of the xanthophyll cycle pigments was investigated, with special focus put on the significance of physical properties of the aggregates formed by inverted lipid micelles, which are necessary for activity of the xanthophyll cycle enzymes. In particular, thickness of the hydrophobic fraction of the aggregates, size of the inverted micelles, suggested by mathematical description of the structures and solubility of Vx and Ddx in various kind of lipids were studied. Obtained results show that the rate of de-epoxidation is strongly dependent on the physicochemical properties of the lipids used. The key role for enzyme activation play non-bilayer lipids and the parameters of inverted micelles such as thickness, fluidity of hydrophobic core and their diameter. The presented results show that MGDG and other non-lamellar lipids like different forms of phosphatidylethanolamine are necessary for the Vx and Ddx de-epoxidation because they provide the three-dimensional structures, which are needed for the binding of de-epoxidases and for the accessibility of Vx and Ddx to these enzymes

Is language an issue? Accuracy of the German computerized diagnostic decision support system ISABEL and cross-validation with the English counterpart.

OBJECTIVES Existing computerized diagnostic decision support tools (CDDS) accurately return possible differential diagnoses (DDx) based on the clinical information provided. The German versions of the CDDS tools for clinicians (Isabel Pro) and patients (Isabel Symptom Checker) from ISABEL Healthcare have not been validated yet. METHODS We entered clinical features of 50 patient vignettes taken from an emergency medical text book and 50 real cases with a confirmed diagnosis derived from the electronic health record (EHR) of a large academic Swiss emergency room into the German versions of Isabel Pro and Isabel Symptom Checker. We analysed the proportion of DDx lists that included the correct diagnosis. RESULTS Isabel Pro and Symptom Checker provided the correct diagnosis in 82 and 71 % of the cases, respectively. Overall, the correct diagnosis was ranked in 71 , 61 and 37 % of the cases within the top 20, 10 and 3 of the provided DDx when using Isabel Pro. In general, accuracy was higher with vignettes than ED cases, i.e. listed the correct diagnosis more often (non-significant) and ranked the diagnosis significantly more often within the top 20, 10 and 3. On average, 38 ± 4.5 DDx were provided by Isabel Pro and Symptom Checker. CONCLUSIONS The German versions of Isabel achieved a somewhat lower accuracy compared to previous studies of the English version. The accuracy decreases substantially when the position in the suggested DDx list is taken into account. Whether Isabel Pro is accurate enough to improve diagnostic quality in clinical ED routine needs further investigation

Impact of chlororespiration on non-photochemical quenching of chlorophyll fluorescence and on the regulation of the diadinoxanthin cycle in the diatom Thalassiosira pseudonana

In diatoms, metabolic activity during long dark periods leads to a chlororespiratory electron flow, which is accompanied by the build-up of a proton gradient strong enough to activate the diadinoxanthin (Ddx) de-epoxidation reaction of the Ddx cycle. In the present study, the impact of chlororespiration on non-photochemical quenching (NPQ) of chlorophyll fluorescence and the regulation of the Ddx cycle in the diatom Thalassiosira pseudonana was investigated by manipulation of the redox state of the photosynthetic electron transport chain during darkness. The response of a transfer of T. pseudonana cells from growth light conditions to 60 min darkness was found to depend on oxygen: in its presence there was no significant reduction of the PQ pool and no de-epoxidation of Ddx to diatoxanthin (Dtx). Under anaerobic conditions a high reduction state of the electron transport chain and a slow but steady de-epoxidation of Ddx was observed, which resulted in a significant accumulation of Dtx after 60 min of anaerobiosis. Unexpectedly, this high concentration of Dtx did not induce a correspondingly high NPQ as it would have been observed with Dtx formed under high light conditions. However, the sensitivity of NPQ to Dtx in cells kept under dark anaerobic conditions increased during reoxygenation and far-red (FR) light illumination. The results are discussed with respect to the activation of the de-epoxidation reaction and the formation of NPQ and their dependence on the extent of the proton gradient across the thylakoid membrane

Removal of chlorinated pesticide contamination by soil washing with sole water

Chlorinated pesticide soil contamination still affects large territories due to past extensive use, poor solubility in water and scarce biodegradability of these agro-chemicals. In particular, this is noticeable for dichloro-diphenyl-trichloroethanes and their derivatives, globally referred as DDX contaminants. Presently, containment or immobilisation is a dominant approach to limit contamination, and remediation has been tried mainly at laboratory scale with contradictory results. Soil washing has been reported as a possible remediation treatment, although environmental effects of employed synthetic co-solvents or surfactants remain unclear. A soil washing treatment with sole water has been set up at laboratory scale, obtaining promising results on a contaminated soil with DDX level of 5050 mg/kg

Self-adjoint oscillator operator from a modified factorization

"By using an alternative factorization, we obtain a self-adjoint oscillator operator of the form Lδ=ddx(pδ(x)ddx)−(x2pδ(x)+pδ(x)−1), where pδ(x)=1+δe−x2, with δ∈(−1,∞) an arbitrary real factorization parameter. At positive values of δ, this operator interpolates between the quantum harmonic oscillator Hamiltonian for δ=0 and a scaled Hermite operator at high values of δ. For the negative values of δ, the eigenfunctions look like deformed quantum mechanical Hermite functions. Possible applications are mentioned.

R2R^2 Gravity in (2+ϵ)(2+\epsilon)--Dimensional Quantum Gravity

We study $R^2$ gravity in $(2+\epsilon)$--dimensional quantum gravity. Taking care of the oversubtraction problem in the conformal mode dynamics, we perform a full order calculation of string susceptibility in the $\epsilon \rightarrow 0$ limit. The result is consistent with that obtained through Liouville approach.Comment: 12 pages; KEK-TH-394, KEK Preprint 94-15, ICRR-Report-318-94-13, UT-Komaba/94-1