Vikram Sunkara

Background: ChatGPT is a large language model (LLM) online chatbot developed by OpenAI and launched in November 2022. Early adoption studies have shown high readiness to use this technology for health-related questions and self-diagnosis. However, the quality and clinical adequacy of health-related responses remain incompletely characterized. This study aimed to explore responses generated by ChatGPT-3.5 and ChatGPT-4.0 to common patient questions regarding scoliosis. Methods: Ten scoliosis-related frequently asked questions (FAQs) were selected from a larger pool of over 250 patient-facing questions compiled from 17 publicly available FAQ webpages and informed by a Google Trends analysis. Questions were harmonized, grouped by theme, and then reduced by rule-based expert review to a final set intended to represent common patient concerns. Results: The median ratings of ChatGPT-3.5 and ChatGPT-4.0 responses ranged from satisfactory, requiring minimal (2) to moderate clarification (3). Across the ten matched questions, no statistically detectable difference was found between models in this study setting (W = 8.0, p = 0.59; Cliff’s δ = −0.12 [95% CI −0.58, 0.40]); however, given the small question set, unblinded rating process, and poor inter-rater reliability, this should not be interpreted as evidence of equivalence, non-inferiority, or comparable model performance. The results apply only to the 10–15 April 2024, online snapshots of ChatGPT-3.5 and ChatGPT-4.0 and should not be generalized to later model iterations. Conclusions: This study should be interpreted as a clinically oriented observational report, intended to inform physician awareness and patient-physician communication rather than validate chatbot accuracy or safety. In this 10–15 April 2024, sample, both model outputs frequently required clinician clarification. Given the small FAQ set, low inter-rater reliability, unblinded design, and single-sample outputs, the findings do not establish equivalence or superiority and apply only to the specific 10–15 April 2024, model snapshots and evaluated questions.

Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating μ-opioid receptors in the gastrointestinal tract. In this study, we present a mathematical model, which integrates the serotonergic and opioid pathways, simulating the interaction between serotonin and opioid signaling within the enteric nervous system (ENS). The model explores the mechanisms underlying OIC, with a focus on the change in adenylyl cyclase (AC) activity, cAMP accumulation, and the distinct functionalities of Endomorphin-2 compared to commonly used pharmaceutical opioids. We study the effects of Morphine, Fentanyl, and Methadone and contrast them with Endomorphin-2. Our findings reveal that opioids do not perturb the signaling of serotonin, but only the activity of AC, suggesting that serotonin levels have no influence on improving opioid-induced constipation. Furthermore, this study reveals that the primary difference between endogenous and pharmaceutical opioids is their degradation rates. This finding shows that modulating opioid degradation rates significantly improves cAMP recovery. In conclusion, our insights steer towards exploring opioid degrading enzymes, localized to the gut, as a strategy for mitigating OIC.

There is a growing interest in generating bimodal, single-cell RNA sequencing (RNA-seq) data for studying biological pathways. These data are predominantly utilized in understanding phenotypic trajectories using RNA velocities; however, the shape information encoded in the two-dimensional resolution of such data is not yet exploited. In this paper, we present an elliptical parametrization of two-dimensional RNA-seq data, from which we derived statistics that reveal four different modalities. These modalities can be interpreted as manifestations of the changes in the rates of splicing, transcription or degradation. We performed our analysis on a cell cycle and a colorectal cancer dataset. In both datasets, we found genes that are not picked up by differential gene expression analysis (DGEA), and are consequently unnoticed, yet visibly delineate phenotypes. This indicates that, in addition to DGEA, searching for genes that exhibit the discovered modalities could aid recovering genes that set phenotypes apart. For communities studying biomarkers and cellular phenotyping, the modalities present in bimodal RNA-seq data broaden the search space of genes, and furthermore, allow for incorporating cellular RNA processing into regulatory analyses.

Healthcare guided by semantic segmentation has the potential to improve our quality of life through early and accurate disease detection. Convolutional Neural Networks, especially the U-Net-based architectures, are currently the state-of-the-art learningbased segmentation methods and have given unprecedented performances. However, their decision-making processes are still an active field of research. In order to reliably utilize such methods in healthcare, explainability of how the segmentation was performed is mandated. To date, explainability is studied and applied heavily in classification tasks. In this work, we propose the Chimeric U-Net, a U-Net architecture with an invertible decoder unit, that inherently brings explainability into semantic segmentation tasks. We find that having the restriction of an invertible decoder does not hinder the performance of the segmentation task. However, the invertible decoder helps to disentangle the class information in the latent space embedding and to construct meaningful saliency maps. Furthermore, we found that with a simple k-Nearest-Neighbours classifier, we could predict the Intersection over Union scores of unseen data, demonstrating that the latent space, constructed by the Chimeric U-Net, encodes an interpretable representation of the segmentation quality. Explainability is an emerging field, and in this work, we propose an alternative approach, that is, rather than building tools for explaining a generic architecture, we propose constraints on the architecture which induce explainability. With this approach, we could peer into the architecture to reveal its class correlations and local contextual dependencies, taking an insightful step towards trustworthy and reliable A.I. Code to build and utilize the Chimeric U-Net is made available under: https://github.com/kenrickschulze/Chimeric-UNet---Half-invertible-UNet-in-Pytorch

We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. Uniquely, this design was based on mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands, recognizing that GPCRs function differently under pathological versus healthy conditions. We now present a novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels associated with parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for NFEPP and fentanyl ligands at different pH values. We found markedly reduced calcium channel inhibition induced by NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl, and enhanced constitutive G-protein activation but lower probability of ligand binding with increasing radical concentrations. By means of molecular dynamics simulations, we also assessed qualitative changes of reaction rates due to additional disulfide bridges inside the GPCR binding pocket. The results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.