Methicillin-resistant Staphylococcus aureus (MRSA) is a critical public health threat within hospitals as well as long-term care facilities. Better understanding of MRSA risks, evaluation of interventions and forecasting MRSA rates are important public health problems. Existing forecasting models rely on statistical or neural network approaches, which lack epidemiological interpretability, and have limited performance. Mechanistic epidemic models are difficult to calibrate and limited in incorporating diverse datasets. We present CALYPSO, a hybrid framework that integrates neural networks with mechanistic metapopulation models to capture the spread dynamics of infectious diseases (i.e., MRSA) across healthcare and community settings. Our model leverages patient-level insurance claims, commuting data, and healthcare transfer patterns to learn region- and time-specific parameters governing MRSA spread. This enables accurate, interpretable forecasts at multiple spatial resolutions (county, healthcare facility, region, state) and supports counterfactual analyses of infection control policies and outbreak risks. We also show that CALYPSO improves statewide forecasting performance by over 4.5% compared to machine learning baselines, while also identifying high-risk regions and cost-effective strategies for allocating infection prevention resources.

Artificial Intelligence (AI) has become essential in modern healthcare, with large language models (LLMs) offering promising advances in clinical decision-making. Traditional model-based approaches, including those leveraging in-context demonstrations and those with specialized medical fine-tuning, have demonstrated strong performance in medical language processing but struggle with real-time adaptability, multi-step reasoning, and handling complex medical tasks. Agent-based AI systems address these limitations by incorporating reasoning traces, tool selection based on context, knowledge retrieval, and both short- and long-term memory. These additional features enable the medical AI agent to handle complex medical scenarios where decision-making should be built on real-time interaction with the environment. Therefore, unlike conventional model-based approaches that treat medical queries as isolated questions, medical AI agents approach them as complex tasks and behave more like human doctors. In this paper, we study the choice of the backbone LLM for medical AI agents, which is the foundation for the agent's overall reasoning and action generation. In particular, we consider the emergent o1 model and examine its impact on agents' reasoning, tool-use adaptability, and real-time information retrieval across diverse clinical scenarios, including high-stakes settings such as intensive care units (ICUs). Our findings demonstrate o1's ability to enhance diagnostic accuracy and consistency, paving the way for smarter, more responsive AI tools that support better patient outcomes and decision-making efficacy in clinical practice.

Artificial intelligence has helped discover a new class of antibiotics that can treat infections caused by drug-resistant bacteria. This could help in the battle against antibiotic resistance, which was responsible for killing more than 1.2 million people in 2019 – a number expected to rise in the coming decades. Testing in mice showed that the new antibiotic compounds proved promising treatments for both Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus – a bacterium that has developed resistance to the drug typically used for treating MRSA infections. "Our [AI] models tell us not only which compounds have selective antibiotic activity, but also why, in terms of their chemical structure," says Felix Wong at the Broad Institute of MIT and Harvard in Massachusetts. Wong and his colleagues set out to show that AI-guided drug discovery could go beyond identifying specific targets that drug molecules can bind to, and instead predict the biological effect of entire classes of drug-like compounds.

Bacterial infections are responsible for high mortality worldwide. Antimicrobial resistance underlying the infection, and multifaceted patient's clinical status can hamper the correct choice of antibiotic treatment. Randomized clinical trials provide average treatment effect estimates but are not ideal for risk stratification and optimization of therapeutic choice, i.e., individualized treatment effects (ITE). Here, we leverage large-scale electronic health record data, collected from Southern US academic clinics, to emulate a clinical trial, i.e., 'target trial', and develop a machine learning model of mortality prediction and ITE estimation for patients diagnosed with acute bacterial skin and skin structure infection (ABSSSI) due to methicillin-resistant Staphylococcus aureus (MRSA). ABSSSI-MRSA is a challenging condition with reduced treatment options - vancomycin is the preferred choice, but it has non-negligible side effects. First, we use propensity score matching to emulate the trial and create a treatment randomized (vancomycin vs. other antibiotics) dataset. Next, we use this data to train various machine learning methods (including boosted/LASSO logistic regression, support vector machines, and random forest) and choose the best model in terms of area under the receiver characteristic (AUC) through bootstrap validation. Lastly, we use the models to calculate ITE and identify possible averted deaths by therapy change. The out-of-bag tests indicate that SVM and RF are the most accurate, with AUC of 81% and 78%, respectively, but BLR/LASSO is not far behind (76%). By calculating the counterfactuals using the BLR/LASSO, vancomycin increases the risk of death, but it shows a large variation (odds ratio 1.2, 95% range 0.4-3.8) and the contribution to outcome probability is modest. Instead, the RF exhibits stronger changes in ITE, suggesting more complex treatment heterogeneity.

In de novo drug design, computational strategies are used to generate novel molecules with good affinity to the desired biological target. In this work, we show that recurrent neural networks can be trained as generative models for molecular structures, similar to statistical language models in natural language processing. We demonstrate that the properties of the generated molecules correlate very well with the properties of the molecules used to train the model. In order to enrich libraries with molecules active towards a given biological target, we propose to fine-tune the model with small sets of molecules, which are known to be active against that target. Against Staphylococcus aureus, the model reproduced 14% of 6051 hold-out test molecules that medicinal chemists designed, whereas against Plasmodium falciparum (Malaria) it reproduced 28% of 1240 test molecules. When coupled with a scoring function, our model can perform the complete de novo drug design cycle to generate large sets of novel molecules for drug discovery.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by FCT (INESC-ID multiannual funding) through the PIDDAC Program funds and under project PEst-OE/EEI/LA0021/2011 and the FP7 Cooperation Work Programme: Food, Agriculture and Fisheries, and Biotechnologies, KBBE-227258 (BIOHYPO project). Quotient Bioresearch received part-funding from the European Union in the scope of BIOHYPO project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: During the elaboration of this manuscript, Ian Morrissey and Daniel Knight were employed by Quotient Bioresearch and belonged to the BIOHYPO European project.