NSIDDx: A Design Framework for Neuro-Symbolic, Practitioner-First Differential Diagnosis in Low-Resource Settings

LLM-based diagnostic systems achieve high semantic accuracy on benchmarks, but open-ended evaluation on clinically uncommon presentations reveals a systematic gap between headline accuracy and verifiable clinical reliability. We evaluate an LLM+rare-disease-RAG pipeline across two cohorts and show that the paradigm produces confident outputs that are frequently unverifiable and systematically resistant to clinician interrogation. We present NSIDDx (Neuro-Symbolic Integrated Differential Diagnosis System), a design framework arguing that DDx systems in low-resource settings must treat the clinician as an active reasoning agent. We instantiate this through a neuro-symbolic pipeline with ternary symptom encoding, contradiction detection, audit strings, and practitioner override - running offline on consumer hardware. We distill five design principles for clinician-in-the-loop clinical NLP and invite the prospective studies needed to validate the claim at scale.

Generating Clinical Vignettes that Preserve Cognitive Formulations

Large language models can generate fluent clinical case vignettes, but fluency alone does not ensure fidelity to a specifiable clinical structure. We introduce FORMA, a theory-grounded framework that compiles a cognitive model of a disorder into a directed weighted graph, samples a person-specific configuration of that graph, and validates whether the generated vignette preserves the specified components and causal links. We instantiate FORMA on Posttraumatic Stress Disorder using the Ehlers and Clark cognitive model, generating 16,500 vignettes across 500 personas, 11 generation models, and three ablation conditions. Evaluation combines an external edge-recovery probe, two clinical experts, a scaled LLM judge, and a clinician user study with 100 licensed practitioners. The cognitive graph is recoverable from full-condition vignettes (MCC = +0.41, AUC = 0.70) but not from zero-shot generation (MCC = +0.01, AUC = 0.50). Experts rate full vignettes substantially higher than zero-shot alternatives, and clinicians perceive them to be human-written 85% of the time, compared with 22% for zero-shot. FORMA also reduces demographic disparity in perceived quality by 1.5-7x. These results show that cognitive formulation can serve as an auditable specification for scalable synthetic clinical text generation. A repository with the data and code is available online: https://github.com/Amit-Oren/FORMA.

Beyond Correctness: Validity-Oriented Evaluation of Biomedical LLM Judges

We propose a scalable, validity-oriented pipeline for evaluating biomedical LLM judges when high-quality human judgments are scarce. First, we augment existing human-labelled biomedical benchmarks with deterministic, metric-grounded mutations that produce auditable preference pairs. Second, we evaluate judges beyond aggregate correctness using three deployment-relevant dimensions: correctness against metric-derived gold labels, robustness under repeated stochastic sampling, and compliance with the requested output format. We use this pipeline to assess Llama-3.1-8B-Instruct under four regimes: (1) base, using the instruct model as is; (2) SFT, distillation-based supervised fine-tuning only; (3) RL, GRPO-based reinforcement learning only; and (4) SFT$\rightarrow$RL, SFT followed by RL. The base and single-stage regimes struggle on structured medical discrimination such as PICO extraction and clinical calculations, whereas SFT$\rightarrow$RL performs best across correctness, compliance, and robustness; gains concentrate on decomposable tasks (PICO, MedCalc), at times matching or outperforming frontier models.

MTDiag: A Multi-Turn Diagnostic Dataset Towards Clinically Meaningful LLM Evaluation

Clinical diagnosis is fundamentally interactive and incremental, yet the dominant paradigm for evaluating Large Language Models (LLMs) in medicine remains static QA benchmarks or template-based dialogues. These benchmarks say little about whether a model can serve as a diagnostic agent in a dynamic clinical encounter, with LLMs showing significant accuracy and reliability degradation in multi-turn settings. To address this issue, we present MTDiag, a large multi-turn diagnostic dialogue dataset constructed from three heterogeneous sources: DDXPlus, MIMIC-IV, and published case reports (AJCR), covering common ED presentations as well as long-tail rare and atypical conditions. All cases are normalized into a canonical schema anchored in the most comprehensive and widely-adopted medical knowledge bases (UMLS concept identifiers, with ICD-10 diagnosis codes). We release the schema, a UserLM-8B-based utterance-generation pipeline, and the physician-validated dataset that converts structured clinical evidence into natural-language utterances. Importantly, we introduce and motivate clinical knowledge-grounded metrics for evaluating LLMs as diagnostic agents, beyond diagnostic accuracy, for the task of multi-turn differential diagnosis.

HealthBench-Psych: A Mental Health Subset of OpenAI's HealthBench

General-purpose health benchmarks increasingly anchor claims about LLM medical performance, but they are not always resolved by clinical specialty, making domain-specific performance hard to isolate. Mental health is of acute public-health concern as millions of people turn to LLMs for psychological support, and most existing evaluations are bespoke academic benchmarks that are difficult to integrate into developer workflows. We introduce HealthBench-Psych and HealthBench-Psych-Hard. We screened HealthBench's 5,000 physician-rubric conversations for mental-health relevance with a transparent LLM-applied rubric, then validated the subset through two rounds of blinded clinician review with concealed known-exclude controls, yielding 610 conversations (12.2% of the corpus). Evaluating 20 frontier and open models under a cross-vendor panel of three LLM judges, we find a statistically tied frontier cluster, measurable refusal behavior in two models, and near-identical rankings across judges ($τ\ge 0.92$). We release the subset, pipeline, model responses, grades, and analysis code as a reusable resource.

BenchBench-Protocol: Evaluating Real-World Wet-Lab Protocol Reasoning and Modification

We introduce BenchBench-Protocol, a benchmark for large language models of 149 protocol-modification tasks recovered from modifications that scientists made to published protocols during real experimental work. Adapting a published protocol to a new experiment is a routine task for a wet-lab scientist, and a correct modification requires accounting for prior choices and downstream steps. Recent life-science benchmarks have moved toward open-ended, rubric-graded tasks, but tasks are typically elicited from experts rather than reconstructed from real-world modifications. BenchBench-Protocol tasks are derived from differences between a published protocol and a version a scientist modified, which provides the basis for the query and the weighted rubric elements for a correct response. The benchmark draws from 96 source protocols across nine domains of wet-lab biology and only includes tasks rated highly after review by domain experts. We evaluate nine closed and open models; Claude Opus 5 scores highest at 59.2% normalized rubric score, with other models between 34.1% and 47.1%, and the benchmark remains unsaturated when taking the best of ten attempts. As models are increasingly helpful in life-sciences research, evaluating them on routine wet-lab tasks becomes correspondingly important. We present BenchBench-Protocol as both a grounded assessment of wet-lab reasoning and evidence for the utility of real-world experiments to construct benchmark tasks.

Sparse Multi-Stage Expert-Agent Routing for Complex Clinical Reasoning

Complex clinical reasoning requires models to update diagnostic hypotheses as new evidence emerges and to coordinate different medical specialities under limited consultation resources. Existing LLM-based clinical reasoning systems typically perform single-pass prediction or rely on fixed multi-agent workflows, making expert participation either static or unnecessarily exhaustive. We propose Sparse Multi-Stage Expert-Agent Routing, a language-based clinical reasoning framework that models diagnosis as a stage-wise routing process. Given progressively available clinical evidence derived from multiple modalities, the framework maintains an evolving case state and adaptively activates a sparse set of medical expert agents, supported by expert-specific memory across stages. To evaluate free-text diagnostic conclusions beyond surface similarity, we further introduce ClinFEScore, a fact-aware semantic evaluation protocol for clinical reasoning outputs. On reconstructed multi-stage cases from MAC and AgentClinic-NEJM, our framework reduces the average number of activated experts from 17.0 to 3.0 whilst maintaining strong fact-level diagnostic quality. On 200 real-world hospital MDT cases, ClinFEScore correlates strongly with clinician judgements (Spearman's $ρ=0.81$; Pearson's $r=0.87$), whilst our method achieves 91.5\% clinician-verified diagnostic accuracy with approximately five expert-agent/LLM calls per case. These results support sparse stage-wise coordination as an efficient and clinically relevant approach to LLM-based clinical reasoning.

Prompting is not enough: supervised baselines and leakage control for measuring shared decision-making with LLMs in pediatric encounters

Objectives: To determine whether zero-shot prompting of a large language model (LLM) is sufficient to detect shared decision-making (SDM) behaviors in real clinical encounters, and whether supervised learning adds value under patient-grouped, nested evaluation. Methods: We analyzed 21 audio-recorded outpatient surgical decision encounters (19 unique patients; 7,566 utterance segments; ~6.1 hours) between families of children with multiple long-term conditions and their surgical providers. Trained coders labeled segments for 12 SDM behaviors (human-human macro Cohen's kappa = 0.695). We compared a zero-shot local LLM (Qwen 2.5 32B), a supervised classifier over frozen sentence embeddings, and their logistic stack, under patient-grouped outer folds with inner cross-fitted thresholds and patient-resampled confidence intervals. Results: The zero-shot LLM reached macro kappa = 0.139 (95% CI 0.111-0.164). The supervised classifier reached kappa = 0.227 (0.186-0.262), a paired improvement of 0.088 (0.051-0.119). A logistic stack of the two reached kappa = 0.242 (0.198-0.284). We identified multiple corpus-specific leakage paths, including grouping sibling recordings separately and allowing labels from an outer held-out patient to enter few-shot exemplars used while fitting downstream models. Conclusion: Zero-shot prompting alone is not sufficient to measure SDM behavior as reliably as a small supervised model, and patient-level grouping alone does not prevent leakage when labeled prompt exemplars are precomputed outside the outer evaluation loop. Reported performance is sensitive to the unit of data splitting and to where labeled exemplars enter the pipeline. External validation is needed before these findings generalize beyond this population, model, prompt, and codebook.

A corpus-specific clinical RAG system matches or outperforms newer frontier LLMs on HealthBench

General-purpose large language models (LLMs) have recently been reported to match or exceed specialized clinical AI tools on medical benchmarks, but such comparisons draw on a narrow set of systems and on benchmarks developed largely in high-income settings. We evaluate VITA, a retrieval-augmented generation (RAG) system purpose-built for contextual knowledge retrieval in India and other low- and middle-income (LMIC) settings. VITA retrieves from a curated corpus of disease-specific guidelines, India-specific antimicrobial resistance data, national formulary constraints, and resource-limited care protocols; its architecture and corpus are proprietary, but the benchmark, the physician-written rubrics, and our full response and scoring outputs are public for independent verification. On 4,023 English-language HealthBench questions (80.5% of the benchmark), scored with a GPT-4.1 judge, VITA ranked first with 51.9% of possible rubric points, ahead of GPT-5.4 (46.1%), o4-mini (44.3%), Gemini 3.1 Pro (42.6%), and Claude Sonnet 4.6 (37.3%), and scored highest on 45.4% of questions. To test robustness to newer models and judge lineage, a 500-question subset was re-run against current-generation models (GPT-5.5, Claude Opus 4.8, Gemini 3.5 Pro, Grok 4.3) and graded by a neutral open-weight judge (DeepSeek-V4-Pro) sharing no lineage with any system tested. Here the gap narrowed to parity: VITA and GPT-5.5 were statistically indistinguishable on mean per-question score, while VITA led on points-weighted score and won the most questions. VITA's advantages in accuracy and completeness persisted under the neutral judge; its communication scores were lower. These results indicate that a purpose-built clinical RAG system remains competitive with frontier LLMs on an open benchmark, consistent with corpus specificity as a design variable that improves grounding at some cost to communication polish.

Artificial Intelligence Can Match Domain Experts in Evidence Extraction and Critical Appraisal of Microbial Oncogenesis Research Publications

Confirmed oncogenic microbes contribute significantly to cancer burden. Identifying novel microbial oncogenicity could yield strategies that will reduce disease burdens. However, relevant evidence is dispersed and infeasible for humans to comprehensively synthesize. LLMs may enable scalable, expert-level systematic evidence synthesis to identify microbe-cancer pairs; however, such capabilities have not yet been demonstrated. Domain experts were recruited to create a dataset to benchmark LLM performance (Gemini 2.5 Pro, Gemini 2.5 Flash, GPT-5, GPT-5 Nano) on 24 research papers using MMTV-LV and breast cancer as a case study. We devised a structured template for evidence extraction and appraisal, consisting of MCQ, Likert-scale, multi-select, and free-text question types (77 items across 24 papers). Agreement between (1) experts and (2) experts and each LLM was determined per question instance using novel metrics. LLMs were assessed by comparing inter-expert and expert-LLM agreement distributions to determine whether LLMs behaved as additional experts by increasing or maintaining inter-expert agreement. Free-text responses were further evaluated qualitatively. Across all question types, LLM responses aligned closely with experts, with GPT-5 and GPT-5 Nano achieving score distributions indistinguishable from experts. Gemini models behaved similarly but were significantly more lenient in applying microbial oncogenesis criteria. Hallucinations were rare. Methodological appraisal and identification of contradictions within full-texts were the most persistent LLM vulnerabilities. GPT-5 and GPT-5 Nano were indistinguishable from experts on structured domain research paper evaluation tasks. This supports use of LLMs for automated systematic evidence synthesis. However, methodological appraisal tasks and contradiction identification in full-texts remain weaknesses requiring strengthening.

RESPClinBench: Benchmarking Multimodal Clinical Decision-Making and Longitudinal Disease Management in Respiratory Specialty Care

Background: Respiratory specialty care requires multimodal interpretation, longitudinal risk assessment, guideline-concordant intervention, and whole-course management, which are poorly represented by examination-oriented medical benchmarks. Objective: To develop RESPClinBench, a real-world scenario-based benchmark for respiratory clinical decision-making, and evaluate seven contemporary large language models across AECOPD-PIM and PNBIM. Methods: RESPClinBench cases were adapted from de-identified respiratory clinical data. Three attending-level respiratory physicians revised cases, reference answers, and atomic clinical-action points, while one senior respiratory specialist performed cross-review and final adjudication. AECOPD-PIM comprised 427 open-ended COPD cases, and PNBIM comprised 196 multimodal pulmonary nodule cases combining chest CT with structured clinical information. Seven models generated 4,361 responses through standardized API inference with temperature 0 and a maximum output length of 8192 tokens. An automated framework calculated the final score as the arithmetic mean of atomic-action recall and rubric-based LLM-as-a-Judge assessment. Results: Across 623 cases, the mean final score was 68.58. Qwen3.6-27B ranked first overall at 71.22, Qwen3.5-397B-A17B led PNBIM at 72.48, and Qwen3.6-27B led AECOPD-PIM at 71.11. Imaging hallucination and serious medical risk occurred in 31.85% and 8.16% of PNBIM responses; medication-safety risk and serious medical risk occurred in 26.93% and 1.44% of AECOPD-PIM responses. Conclusions: RESPClinBench identifies task-specific limitations in multimodal pulmonary nodule assessment and longitudinal COPD management. Combining explicit clinical-action coverage, holistic evaluation, and independent safety flags provides a clinically grounded basis for model selection and prospective validation.

BrainBench: Benchmarking Large Language Models for Comprehensive EEG Understanding

Electroencephalography (EEG) analysis extends beyond assigning predefined labels to recordings; it requires workflows connecting natural-language instructions, signal processing, quantitative evidence, and scientific interpretation. We term this capability \emph{comprehensive EEG understanding}. Existing evaluations, however, primarily target isolated decoding tasks or system-specific demonstrations, leaving the competence of large language models (LLMs) insufficiently quantified. We introduce \benchmarkname{}, a unified benchmark for comprehensive, instruction-conditioned EEG understanding. It comprises four subsets---Foundational Analysis, Sleep Assessment, Neurocognitive Assessment, and Physiological Integration---covering 17 datasets, \numcases{} tasks, and over \numinstances{} real-data instances. Given an instruction and EEG recordings with optional physiological signals, a system must perform the analysis and produce a scientifically grounded report and, when required, artifacts. Outputs are assessed through numerical, categorical, set, sequence, semantic, and artifact validation. We evaluate \nummodels{} representative LLMs across more than 100K executions under two paradigms: autonomous code execution with CodeAct and structured agentic analysis with BrainAgent. Results vary substantially across models, subsets, difficulty levels, and execution paradigms, showing that EEG competence depends on the model and its operationalization. \benchmarkname{} provides a reproducible testbed for advancing LLM-based EEG understanding. The code and benchmark will be released soon, with evaluation results continuously updated.

Quantization Effects on Biomedical LLM Reliability

When decoder language models are used as classifiers, predicted class probabilities depend on implementation choices, including the prompt template, verbalizer (label-to-token mapping), and scoring rule, that are rarely treated as experimental variables. We present a controlled evaluation of three Mistral-7B variants (Base, BioMistral, and Instruct) on PubMed RCT sentence classification (n=2000) under FP16, INT8, and INT4 precision using four answer-text prompt templates. Our primary finding is that the probability extraction protocol dominates apparent calibration. Switching from summed to mean token log-likelihood scoring reverses the calibration ranking between models: BioMistral average expected calibration error increases from 0.097 to 0.289, whereas Instruct decreases from 0.237 to 0.096, while accuracy changes by less than 1 percentage point for the specialized models but 4-6 percentage points for the base model. Prompt template choice produces accuracy differences of 7-24 percentage points, comparable to or larger than model-level effects. On one template, BioMistral outperforms Instruct although the overall mean favors Instruct by only 1.3 percentage points. For BioMistral and Instruct, INT8 quantization changes accuracy and F1 by only 1-2 percentage points relative to FP16, whereas the base model shows larger INT8 effects on some templates (up to +4.2 percentage points). INT4 produces heterogeneous but non-catastrophic effects. Temperature scaling reduces expected calibration error under summed scoring for both models but only for that scoring rule. A fine-tuned PubMedBERT reference achieves 82.7% accuracy but uses about 176000 labeled training examples, precluding direct comparison. These results demonstrate that prompt template design and scoring normalization are first-order experimental decisions when evaluating decoder language model calibration.

Consensus Measures for Unstructured Biomedical Text Annotations

Biomedical literature is increasingly mined for knowledge beyond the questions it was written to answer. Because the target concepts are not known in advance, annotators prefer open-ended labels, whose agreement is hard to quantify. We study soft inter-rater reliability for annotators providing unstructured texts for biomedical annotation tasks. Synthetic experiments show that soft reliability can be quantified using a variety of semantic equivalence measures, and that the choice of measure affects failure modes of the estimation. Embeddings are scalable, but limited when differentiating similar but distinct concepts. Large language models are promising, but limited by scalability for estimating agreement by chance. Finally, we suggest measures based on natural language inference as a sensible compromise.

MyMentorLLM: A psychotherapy GenAI environment with multimodal voice/text patients, trainees and experts for deliberate practice

Psychotherapists need repeated training and supervision by experts; however, scalability is problematic. Here we present MyMentorLLM, a multimodal voice- and text-based simulation environment for deliberate practice, used to generate 2,100 complete Cognitive Behavioural Therapy (CBT) training sessions. Each session links a DSM-5-TR-grounded patient (with major depressive, generalised anxiety or borderline personality disorder), a therapist-in-training and an expert supervisor. As an initial implementation, we adopted CBT because its structured procedures and competency-based supervision facilitate standardised simulation and evaluation. Sessions were analysed for emotional dynamics, therapeutic competence and diagnostic accuracy. Simulated patients expressed disorder-congruent emotional profiles, which trainee therapists mirrored as in real human counselling. The quality of supervision differed across LLMs: while most models overestimated trainees' competences, native speech-to-speech was closest to human scores. Supervisors' feedback led to better diagnoses in simulated psychotherapists in 5 out of 7 LLMs, and symptom identification accuracy increased with model size. This work shows that simulation of deliberate practice is possible for CBT training, although patient fidelity, calibration of supervisors, and harmful feedback should be evaluated together.

MyoCardBench: A Real-World Data Benchmark for Evaluating Large Language Models in Clinically Authentic Cardiovascular Care Scenarios

Background: Most medical large language model (LLM) benchmarks focus on examination knowledge or isolated tasks and may not reflect the longitudinal, multimodal, and safety-critical workflow of cardiovascular care. Objective: To develop MyoCardBench, a real-world benchmark spanning the cardiovascular care continuum, and assess LLM performance across clinical dimensions and specialist tasks. Methods: MyoCardBench includes 2,263 items from 13 task-specific datasets derived from de-identified cardiovascular records and examination data. Sixteen cardiology physicians conducted annotation and reference construction, followed by cross-review from two senior cardiologists. Seven LLMs generated 15,841 outputs under standardized zero-shot settings. Open-ended tasks were evaluated using key-point coverage and holistic clinical quality, while CardioEthics was scored by accuracy. Results: GPT-5.4 achieved the highest macro-average (62.55) and item-weighted mean (62.19), followed by Gemini 3.1 Pro (59.95) and Qwen 3.6 27B (59.72). GPT-5.4 ranked first in all three dimensions. CardioAuxReport performed best (86.38), whereas CardioECGRead (17.25) and CardioEthics (17.34) were lowest. The largest gaps between holistic clinical quality and key-point coverage occurred in CardioComm (52.71), CardioEmergRescue (52.05), and CardioTreatPlan (48.80). Conclusions: To our knowledge, MyoCardBench is the largest real-world, multi-task benchmark for LLM evaluation across the cardiovascular care continuum and offers the broadest coverage of clinically authentic cardiology scenarios reported to date. It provides a rigorous framework for identifying model strengths, clinically important omissions, and priorities for future development.

Accuracy and Reliability of Large Language Models in Cosmetic Chemistry and Skin Health: A Benchmarking Study

As consumers increasingly turn to AI chatbots for skincare advice, the technical accuracy of Large Language Models (LLMs) in cosmetic chemistry remains largely under-evaluated. We benchmarked 14 LLMs on a structured set of topics related to cosmetic chemistry, including the chemical properties of specific cosmetic ingredients and common cosmetic scenarios that may be of interest to consumers. Web search was disabled throughout to assess each model's internalized knowledge rather than its internet retrieval capacity. Overall performance was poor, with the most pronounced deficits in quantitative reasoning and structural identification tasks. While models handled general skincare questions with reasonability, responses consistently lacked the technical depth required for informed consumer decision-making. Notably, conversation with AI can pose a risk: outputs that sound authoritative but contain technical errors are less likely to generate skepticism compared to responses that explicitly acknowledge uncertainty. These findings suggest that general-purpose LLMs, trained predominantly on unverified public data, are currently not reliable sources of cosmetic chemistry information. Progress on two fronts, fine-tuning verified chemical and dermatological datasets, and substantial improvements to algorithmic reasoning, will likely be needed before these tools can be considered as resources for public use.

The complexities of patient-centred conversational artificial intelligence

Consumer-facing health chatbots powered by large language models (LLMs) are increasingly used for symptom assessment. However, chatbot development and evaluation often rely on cooperative, articulate, simulated patients. We analysed 2,053 real patient-chatbot conversations and found that communication patterns and expression of emotions vary widely across users. We developed a patient simulator that separately models clinical content, emotional state, conversational strategy, and communication style. In a Turing-inspired evaluation of realism with 15 human graders, simulated conversations were nearly indistinguishable from real ones, with human graders achieving an accuracy of 55%. We used five distinct patient personae, across 1,164 clinician-graded cases, to evaluate the performance of four LLMs in urgency assessment. We found that communication style can significantly alter triage outcomes. Patient-centred conversational artificial intelligence must accommodate communication diversity: systems designed for idealised, rather than realistic, interactions risk underperforming and amplifying health disparities when deployed in the real world.

MentalHospital: A Virtual Environment for Evaluating Psychiatric Clinical Encounters

Large language models (LLMs) have shown strong performance on isolated psychiatric tasks, including dialogue, diagnosis, and treatment planning, yet existing benchmarks rarely simulate complete psychiatric clinical encounters. We introduce $\textbf{MentalHospital}$, a virtual evaluation environment for LLM-based psychiatric clinical encounters. MentalHospital instantiates the Subjective Interviewing, Objective Examination, Diagnostic Assessment, and Treatment Planning (S.O.A.P.) workflow, using skill-augmented standardized patients constructed from 1,193 de-identified psychiatric electronic health record (EHR) cases spanning all major ICD-11 categories and 76 disorders. Each encounter is assessed through a dual-track protocol that combines objective comparison against EHR-derived references with subjective assessment of clinical process quality. To scale specialist judgment, we develop $\textbf{MentalEval}$, five domain-specific evaluators covering communication empathy, interviewing professionalism, clinical-note quality, diagnostic rigor, and treatment appropriateness, trained with rubric-grounded SFT and expert-guided DPO. Survey responses from 22 clinicians support MentalHospital's clinical fidelity (3.88/5), while MentalEval achieves strong expert alignment with an average QWK of 0.944. Benchmarking shows that even the strongest LLM trails clinicians by 37.28 percentage points in objective psychiatric competence, with mental status assessment as a key bottleneck.

A safety-oriented hypothetico-deductive framework for AI-assisted differential diagnosis

Diagnostic error is a major threat to patient safety, yet current large language model (LLM) systems often treat diagnosis as a one-shot prediction task, lacking safeguards against missed high-risk alternatives or rigorous verification of their reasoning. Here, we present AegisDx, a safety-oriented framework for hypothetico-deductive clinical reasoning. AegisDx coordinates specialized LLM components through role-specific contracts, structured intermediate outputs, evidence-retrieval interfaces, and verification gates to generate broad differential diagnoses, enforce explicit screening for dangerous "must-not-miss" conditions, verify reasoning against grounded medical evidence, and structure actionable next steps. We evaluated AegisDx across three layers. On literature-derived case reports from NEJM and JAMA, with GPT-oss-120B as the shared backbone, Top-3 diagnostic accuracy was 59.9% versus 52.1% for the standalone LLM on JAMA cases and 62.7% versus 51.4% on NEJM cases. On cases from Annals of Emergency Medicine, Top-3 accuracy was 85.7% versus 68.6%; against physician-consensus must-not-miss diagnosis sets, AegisDx captured at least one such condition among its top three diagnoses in 78.0% of cases versus 52.0%. In a blinded physician evaluation of 43 real-world emergency department notes from the Yale New Haven Health System compared against GPT-5, AegisDx improved the physician-rated composite safety score from 4.31 to 4.55 on a 5-point scale (adjusted p = 2.1x10^-4), with qualitative gains in must-not-miss identification and reasoning safety. Our findings suggest that engineering diagnostic AI as a safety-oriented reasoning framework, rather than optimizing raw predictive accuracy alone, can provide a safer, more transparent, and clinically meaningful layer of bedside decision support for acute care workflows.

Optimizing Large Language Models for Causality Assessment in Pharmacovigilance: Developing a Performance Metric as Objective for Bayesian Hyperparameter Optimization

Background: Growing individual case safety report (ICSR) volumes have intensified demand for scalable automated causality assessment. Large Language Models (LLMs) show promise, yet performance on clinically demanding tasks remains suboptimal and inference-time hyperparameter optimization has not been investigated. Objective: To develop a Gaussian Process (GP)-compatible optimization objective and investigate whether temperature optimization improves LLM-expert agreement on Naranjo causality assessment of FAERS ICSRs. Methods: Expert causality assessments were performed on 723 stratified FAERS cases. OpenAI's GPT-5.2 was evaluated using chain-of-thought (CoT) prompting. Four composite metrics were developed: Weighted Cosine Similarity (WCS), Information-Weighted Agreement Score (IWAS), Entropy-Weighted Agreement and Cosine Similarity Score (EWACS), and Consensus-Weighted Cosine Similarity (CWCS) and Bayesian optimization using a GP surrogate with Probability of Improvement (PoI) acquisition was applied across temperature [0, 2]. Results: GPT-5.2 outperformed prior biomedical LLMs at baseline (T = 0), achieving 74.1% agreement on question 5 and 65.4% on question 10 of Naranjo algorithm. Entropy analysis identified these as the sole informative optimization targets. Temperature showed no systematic population-level effect (\b{eta} = 0.002, p = 0.959). EWACS-guided Bayesian optimization improved causality classification agreement from 45.0% to 72.0% (+27 pp), with the largest gain in Doubtful cases (+42.9 pp). Conclusion: EWACS was identified as the optimal GP-compatible metric. The absence of a universal temperature optimum indicates LLM performance is driven primarily by ICSR content, yet case-specific temperature selection produced meaningful improvements, supporting temperature optimization for LLM-assisted pharmacovigilance.

Evaluating AI Generated Summaries for Cancer Patients

Large language models (LLMs) are increasingly being integrated into digital health platforms to generate summaries of complex medical data. Although these models can improve patient engagement and communication, these systems also raise concerns about accuracy, faithfulness, and safety in clinical contexts. In this study, we evaluate AI-generated summaries within a cancer patient care application using a dual assessment framework. Human domain experts, including oncology clinicians and patient-facing care staff, provided ground-truth evaluations of summary quality along dimensions of accuracy, clinical relevance, and readability. In parallel, we employed LLMs serving as evaluators (LLM-as-a-judge). Some limitations were identified in the generated summaries e.g., occasional omissions and minor inaccuracies. These were systematically analyzed and used to iteratively improve prompt design, grounding, and safety guardrails.

Seeing Through Multiple Views: Parameter-Efficient Fine-Tuning via Selective Neurons for Consistent Radiology Report Generation

Recent years have seen substantial advances in radiology report generation (RRG), yet existing approaches predominantly adopt direct feature fusion when handling multi-view X-ray images. Such approaches overlook the potential clinical inconsistencies and inaccuracies arising when a single model processes different views, adversely impacting performance and clinical reliability. To this end, we introduce View-PNDF (View-specific Pattern Neuron Detection and Fine-tuning), a parameter-efficient framework that fosters view-consistent report generation from a neuronal perspective. Specifically, View-PNDF comprises: (i) a view-specific neuron detection module identifying neurons responsive to particular views, (ii) a verification module quantifying the existence of these neurons, and (iii) a selective fine-tuning strategy strengthening detected neurons while preserving view-agnostic representations. By updating only view-specific neurons, View-PNDF achieves consistent diagnoses across different views with reduced computational costs. Subsequently, we employ Large Language Models (LLMs) to consolidate the view-specific reports into a complete radiology report. Furthermore, we use traditional Natural Language Generation (NLG) metrics-based assessment on integrated reports for baseline comparison and employ LLM-based assessment (e.g., GPT-4o) on view-specific reports to capture clinical significance. Extensive experiments on two medical RRG benchmarks demonstrate that View-PNDF substantially improves view-specific chest X-ray report generation quality while maintaining robust general-view performance.

Expert Evaluation of Clinical AI Tools on Real Point-of-Care Clinical Queries

Physicians now pose millions of clinical questions to AI tools each week, yet these tools are evaluated largely on hypothetical or exam-style questions, not those actually asked in practice. We report a blinded evaluation built on 620 Real-world Point-Of-Care Queries (Real-POCQi) submitted to the OpenEvidence (OE) platform by physicians spanning 30 specialties, as well as 187 questions from HealthBench. 149 practicing physicians across 36 states made head-to-head comparisons between answers from three frontier general-purpose models (Claude Opus 4.8, Gemini 3.1 Pro, and GPT-5.5) and a specialized clinical tool (OE), with graders matched to each question's specialty. When comparing answers along five dimensions relevant to clinical decision support -- accuracy, clinical utility, source quality, verifiability, & completeness -- physicians scored the specialized tool highest on all axes; in the primary analysis on Real-POCQi, win differences (margins between win and loss rates) ranged from 25 to 39 percentage points (p<0.001). Results remained consistent in sensitivity analyses stratifying by citation display, answer length, OE-user status, and Real-POCQi versus HealthBench. In parallel, LLM judges were found to systematically differ from expert judges, though both generally agreed on the best model. These findings underscore two conclusions: (i) AI tool evaluations should reflect real-world query distributions and use expert judges that mirror the specialization defining modern medicine and (ii) the consistent advantage of the specialized tool over general-purpose models does not necessarily mean that the latter cannot serve similar purposes, but that targeted engineering and customization can yield meaningful gains in performance for its users. We release Real-POCQi as a public benchmark, as well as the prespecified statistical analysis for reproducing results of this study.

An ambiguity taxonomy for evaluating large language model performance on clinical registry abstraction: a multi-site prospective study

Objective: To evaluate large language model (LLM) performance on unprocessed electronic medical record (EMR) data for clinical registry abstraction. Methods: We evaluated LLM performance answering registry questions for the American College of Cardiology National Cardiovascular Data Registry (ACC NCDR). In a pilot study at an academic medical center, the model identified candidate data sources for each registry question and experienced abstractors used these results to define question-specific document sets. In a validation study at a second center with a second ACC NCDR registry, the LLM answered questions using the question-specific document sets. Before reviewing any output, two abstractors independently established the ground truth and assigned each question to one of six categories, ordered by the ambiguity and clinical reasoning required to resolve it: Medication/Event Flag, Binary Clinical Presence, Administrative, Quantitative Laboratory/Physiologic, Clinical Interpretation, and Event Timing. Results: The analytical sample comprised 9,430 abstractor answers reconciled to 4,715 consensus answers (501 pilot; 4,214 validation). In the pilot, candidate data sources per question averaged between 14.6 (SD 13.9) for demographics and 89.2 (SD 56.1) for history and risk factors. In validation, human inter-rater agreement was approximately 98\% while 87\% of LLM answers exactly matched consensus, 2\% partially, and 9\% did not. Mean question-level accuracy was 91.5\% (SD 13.4\%) across 157 questions with at least 20 answers, and declined as ambiguity increased, from 96\% for Medication/Event Flag to 62\% for Event Timing questions. Conclusions: LLMs answering clinical registry questions on unprocessed EMR data achieved far lower accuracy than human abstractors. LLM accuracy fell steadily as ambiguity and the level of required clinical reasoning increased.

T2D-Bench: Evidence-Gated Evaluation of LLM Outputs for Type 2 Diabetes Using a Multi-Layer Clinical-Lifestyle Knowledge Graph

Large language models (LLMs) can produce clinically fluent recommendations for type 2 diabetes while failing to satisfy guideline constraints or explicitly justify lifestyle-related glycemic claims. We present T2D-Bench, a reproducible benchmark and evidence-gated evaluation framework for testing whether LLM outputs satisfy explicit, graph-checkable evidence requirements. T2D-Bench is built on a multi-layer clinical-lifestyle knowledge graph that combines a biomedical spine (UMLS, DrugBank, SIDER), computable ADA Standards of Care rules, and lifestyle knowledge connected through a mechanistic bridge to glycemic laboratory effects. Across 100 structured vignettes spanning diagnosis, medication safety, and adversarial lifestyle conflicts, baseline outputs failed benchmark-defined evidence-path checks in 35% of cases for GPT-4o-mini and 33% for GPT-4o. The evidence gate detects unsupported omissions and uses constrained revision to bring outputs into verifier-level compliance with benchmark-defined evidence requirements. These results show that computable evidence constraints can make unsupported clinical omissions explicit, measurable, and correctable in diabetes-focused LLM outputs.

Trust but Verify: Mitigating Medical Hallucinations via Post-Hoc Adversarial Auditing and Multi-Agent Feedback Loops

Large Language Models (LLMs) are increasingly deployed in healthcare settings, yet their tendency to hallucinate poses risks when clinical decisions are involved. This study examine whether LLMs recommend recently banned or withdrawn pharmaceuticals when answering clinical questions and tests an agent-based method for reducing such errors. We developed a five-agent "Trust but Verify" system using a single LLM backbone. To measure regulatory knowledge obsolescence, we created an adversarial dataset of 103 clinical MCQs where historically correct answers now refer to banned substances. This scale ensures statistical significance across various therapeutic classes. We evaluated three open-access model families (GPT-OSS, Llama-3, Falcon-3) under vanilla and agentic conditions. Performance was measured via pointwise score, label accuracy, Hallucination Error Rate (HER), and Component Fidelity (CF) score. We also observed clinical safety regression in proprietary models. In default configurations, all models showed high hallucination rates, consistently selecting banned drugs that matched training data patterns. Our proposed agentic architecture reduced HER by approximately 53% across models. Pointwise scores shifted from -0.25 (unsafe recommendation) toward 0.0 (appropriate refusal). The safety audit intercepted dangerous outputs even when models' parametric knowledge favored the banned substance. The proposed multi-agent framework offers a model-agnostic method for enforcing regulatory compliance that prioritizes patient safety over fluent text generation. Our work demonstrates a practical approach for deploying autonomous AI systems in safety-critical healthcare settings. It shows how real-time regulatory data can be integrated into LLM pipelines to support clinical decision-making.

PATHFinder Agent for Tailored Prenatal Care

Prenatal care is an important preventive service designed to improve outcomes for pregnant individuals. The American College of Obstetricians and Gynecologists (ACOG) recently introduced guidelines advocating tailored prenatal care, called PATH (Plan for Tailored Healthcare). We present PATHFinder Agent(Planner for Appropriate Tailored Healthcare), an end-to-end conversational agentic system that gathers patient health and social context through structured dialogue, curates individualized prenatal care plans aligned with PATH guidelines, and surfaces community resources from Michigan 211. The system features a four-stage workflow spanning patient intake, dynamic interaction, plan synthesis, and clinician oversight. We evaluate frontier large language models (LLMs) on expert-curated rubrics across five clinical dimensions, finding that GPT-5.2 achieves the highest average score (77.6\%) while identifying key gaps in antenatal testing recommendations. We discuss future validation through human participant studies and randomized controlled trials.

Ten Headache Specialists versus Artificial Intelligence for Clinical Literature Summarization: A Critical Evaluation and Comparison

Summarizing the latest medical literature to guide clinical decision-making is essential for evidence-based medicine and high-quality patient care. Yet clinicians face increasing challenges due to limited time with patients and a rapidly growing volume of published articles. Although retrieval-augmented large language models (LLMs) have shown promise in clinical summarization, human evaluations of their effectiveness in synthesizing broader scientific literature and direct comparisons to expert-written syntheses remain scarce. We constructed a RAG-based agentic AI framework using three state-of-the-art LLMs: Sonnet, GPT-4o, and Llama 3.1. A headache specialist created 13 questions, three for prompt optimization and ten for evaluation. Ten headache specialists across the United States and Canada each wrote a summary for one question, yielding four summaries per question (expert, Sonnet, GPT-4o, and Llama). The experts, blinded to authorship, critically evaluated the summaries, excluding the topic for which they wrote a summary, based on correctness, completeness, conciseness, and clinical utility, scoring each from 1 to 10 using standardized rubrics. They also ranked the summaries by preference and indicated whether they believed each summary was written by an expert or an LLM. Our study, comparing LLM- and expert-written literature summaries evaluated by headache specialists, showed that expert-written summaries were preferred, although experts sometimes found it challenging to distinguish between human- and AI-generated summaries. We also identified key expert-valued features beyond standard evaluation metrics that can guide future refinement of both human and AI literature summarization pipelines.

Gender-Dependent Diagnostic Substitution in LLM Medical Triage: Same Symptoms, Unequal Urgency

We investigate whether large language models produce different medical triage recommendations for identical neurological symptoms when only the patient's stated gender and age vary. Using three model families--Gemini 3.5 Flash, Claude Sonnet 4.6, and GPT-5.4-mini--we present a standardized symptom profile (persistent headache, blurred vision, morning nausea, visual disturbances) across seven demographic conditions: three age groups (25, 38, 65) x two genders (male, female), plus a gender-unspecified baseline (n = 30 per condition per model, 630 total trials). We find a stark, systemic gender-dependent triage disparity: young women receive significantly lower emergency room (ER) referral rates than age-matched men (Gemini: 0% vs. 23.3%; Claude: 6.7% vs. 96.7%; GPT: 6.7% vs. 66.7%, all p < 0.001). The disparity disappears at age 65 for all models. The primary mechanism is diagnostic substitution: the models anchor on a gender-associated diagnosis, preferentially classifying young women with Idiopathic Intracranial Hypertension (IIH)--a condition epidemiologically linked to women of childbearing age--while diagnosing men with generic increased intracranial pressure with space-occupying lesions in the differential. This diagnostic closure routes female patients to lower-urgency care (outpatient doctor appointments) despite comparable severity ratings (7-9/10). Our findings demonstrate that clinical LLMs replicate documented human clinical biases by using epidemiological priors to suppress triage urgency, suggesting that AI triage engines must decouple urgency assessment from probabilistic diagnostic priors. We release all code, prompts, and raw results.