Evaluating ChatGPT as a Patient Education Tool for COVID-19-Induced Olfactory Dysfunction.

Objective: While most patients with COVID-19-induced olfactory dysfunction (OD) recover spontaneously, those with persistent OD face significant physical and psychological sequelae. ChatGPT, an artificial intelligence chatbot, has grown as a tool for patient education. This study seeks to evaluate the quality of ChatGPT-generated responses for COVID-19 OD. Study Design: Quantitative observational study. Setting: Publicly available online website. Methods: ChatGPT (GPT-4) was queried 4 times with 30 identical questions. Prior to questioning, Chat-GPT was "prompted" to respond (1) to a patient, (2) to an eighth grader, (3) with references, and (4) no prompt. Answer accuracy was independently scored by 4 rhinologists using the Global Quality Score (GCS, range: 1-5). Proportions of responses at incremental score thresholds were compared using χ 2 analysis. Flesch-Kincaid grade level was calculated for each answer. Relationship between prompt type and grade level was assessed via analysis of variance. Results: Across all graded responses (n = 480), 364 responses (75.8%) were "at least good" (GCS ≥ 4). Proportions of responses that were "at least good" (P < .0001) or "excellent" (GCS = 5) (P < .0001) differed by prompt; "at least moderate" (GCS ≥ 3) responses did not (P = .687). Eighth-grade level (14.06 ± 2.3) and patient-friendly (14.33 ± 2.0) responses were significantly lower mean grade level than no prompting (P < .0001). Conclusion: ChatGPT provides appropriate answers to most questions on COVID-19 OD regardless of prompting. However, prompting influences response quality and grade level. ChatGPT responds at grade levels above accepted recommendations for presenting medical information to patients. Currently, ChatGPT offers significant potential for patient education as an adjunct to the conventional patient-physician relationship.

Dynamic chromatin architecture identifies new autoimmune-associated enhancers for IL2 and novel genes regulating CD4+ T cell activation.

Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact cis-regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk. We localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 co-stimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured transcript levels, chromatin accessibility, and promoter-cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified ~1200 protein-coding genes physically connected to accessible disease-associated variants at 423 GWAS signals, at least one-third of which are dynamically regulated by activation. From these maps, we functionally validated a novel stretch of evolutionarily conserved intergenic enhancers whose activity is required for activation-induced IL2 gene expression in human and mouse, and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes controlling CD4+ T cell function and genes involved in human inborn errors of immunity, and we pharmacologically validated eight implicated genes as novel regulators of T cell activation. These studies directly show how autoimmune variants and the genes they regulate influence processes involved in CD4+ T cell proliferation and activation.

Artery Grafting for Arterial Anastomoses in Head and Neck Free Tissue Transfer Reconstruction.

BACKGROUND: Vessel grafting is an important technique in head and neck free tissue transfer (FTT) reconstruction when a tension-free anastomosis is not otherwise feasible. To our knowledge, there are limited data regarding interposition artery grafts for arterial anastomoses in head and neck reconstruction. Here, we present a multi-institutional cohort of arterial interposition grafts for FTT reconstruction for head and neck defects. METHODS: A retrospective review was conducted at four tertiary care institutions for patients who underwent FTT reconstruction for head and neck defects which utilized an interposition artery graft for the arterial anastomosis. Charts were reviewed for type and length of artery grafts harvested, surgical indication, indication for artery graft, types of flaps harvested, and various preoperative characteristics (including history of radiation or previous FTT reconstruction surgery). Postoperative complications within postoperative day 30 were measured and reported. RESULTS: Nine patients met inclusion criteria. The lateral circumflex femoral artery (either transverse or descending branches) (n = 3) and facial artery (n = 3) were the most commonly harvested arteries. The scalp (n = 5) was the most common primary defect site. Seven grafts were harvested initially and in a planned fashion, while two were harvested as salvage techniques (either for flap salvage or vein graft failure). In planned grafts, arteries were the preferred interposition grafting method due to either size match preferences (n = 4) or similarities in wall thickness (n = 3) between graft and recipient artery. There were no reported cases of unplanned readmission, postoperative hematoma, fistula formation, wound infection, or donor site morbidities. Two patients required unplanned return to the operating room for flap compromise, both of which ultimately resulted in flap failure secondary to clot formation at both arterial and venous anastomoses. CONCLUSIONS: When arterial pedicle length is insufficient, interposition artery grafting is both a feasible and viable technique to achieve tension-free arterial anastomoses for select cases of highly complex head and neck free tissue reconstruction.

T cells promote distinct transcriptional programs of cutaneous inflammatory disease in human skin structural cells.

T cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cell activity precipitates tissue pathology that occurs alongside disease-associated alterations of structural cell subsets, but the mechanisms by which T cells promote these changes remain unclear. We show that subsets of circulating and skin-resident CD4+ T cells promote distinct transcriptional outcomes in human keratinocytes and dermal fibroblasts that correspond with divergent T cell cytokine production. Using these transcriptional signatures, we identify T cell-dependent outcomes associated with inflammatory skin disease, including a set of Th17 cell-induced genes in keratinocytes that are enriched in the skin during psoriasis and normalized by anti-IL-17 therapy, and a skin-resident T cell-induced gene module enriched in scleroderma-associated fibroblasts. Interrogating clinical data using T cell-derived structural cell gene networks enables investigation of the immune-dependent contribution to inflammatory disease and the heterogeneous patient response to biologic therapy.

Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.

In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in C. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.

Obesity and Survival After Immune Checkpoint Inhibition for Head and Neck Squamous Cell Carcinoma.

Importance: For patients treated with immune checkpoint inhibitors (ICIs), recent data suggest that obesity has a beneficial effect on survival outcomes in various cancer types. Reports on this association in head and neck cancer are limited. Objectives: To compare overall survival (OS) to 5 years and functional outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with ICIs based on pretreatment body mass index (BMI). Design, Setting, and Participants: This retrospective population-based cohort study used data obtained from the TriNetX Global Collaborative Network database to identify patients with HNSCC who received ICI treatment between January 1, 2012, and December 31, 2023, resulting in a total of 166 patients (83 with BMI of 20.0-24.9 [normal BMI] and 83 with BMI of ≥30.0 [obesity BMI]) after propensity score matching (PSM) for pretreatment medical comorbidities and oncologic staging. Exposure: Normal BMI vs obesity BMI. Main Outcomes and Measures: Overall survival and functional outcomes (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) were measured to 5 years after ICI treatment and compared between patients with obesity BMI and normal BMI. Additional analyses compared OS and functional outcomes in the cohort with normal BMI and cohorts with overweight BMI (25.0-29.9) and underweight BMI (<20.0). Results: Among the 166 patients included in the PSM analysis (112 men [67.1%]; mean [SD] age, 62.9 [15.4] years), obesity BMI was associated with significantly improved OS at 6 months (hazard ratio [HR], 0.54 [95% CI, 0.31-0.96]), 3 years (HR, 0.56 [95% CI, 0.38-0.83]), and 5 years (HR, 0.62 [95% CI, 0.44-0.86]) after ICI treatment, compared with patients with normal BMI. Obesity BMI was also associated with decreased risk of gastrostomy tube dependence at 6 months (odds ratio [OR], 0.41 [95% CI, 0.21-0.80]), 1 year (OR, 0.41 [95% CI, 0.21-0.78]), 3 years (OR, 0.35 [95% CI, 0.18-0.65]), and 5 years (OR, 0.34 [95% CI, 0.18-0.65]). Obesity was also associated with decreased risk for tracheostomy dependence at 1 year (OR, 0.52 [95% CI, 0.28-0.90]), 3 years (OR, 0.45 [95% CI, 0.45-0.90]), and 5 years (OR, 0.45 [95% CI, 0.45-0.90]). There were no differences in rates of dysphagia or immune-related adverse events between cohorts at any points. Conclusions and Relevance: Using population-level data for patients with HNSCC treated with ICIs, these results suggest that having obesity was associated with improved 6-month, 3-year, and 5-year OS compared with having normal BMI. Additionally, obesity was associated with decreased gastrostomy and tracheostomy tube dependence compared with normal BMI. Further investigation is required to understand the mechanism of these findings.

Chatbots as Patient Education Resources for Aesthetic Facial Plastic Surgery: Evaluation of ChatGPT and Google Bard Responses.

Background: ChatGPT and Google Bard™ are popular artificial intelligence chatbots with utility for patients, including those undergoing aesthetic facial plastic surgery. Objective: To compare the accuracy and readability of chatbot-generated responses to patient education questions regarding aesthetic facial plastic surgery using a response accuracy scale and readability testing. Method: ChatGPT and Google Bard™ were asked 28 identical questions using four prompts: none, patient friendly, eighth-grade level, and references. Accuracy was assessed using Global Quality Scale (range: 1-5). Flesch-Kincaid grade level was calculated, and chatbot-provided references were analyzed for veracity. Results: Although 59.8% of responses were good quality (Global Quality Scale ≥4), ChatGPT generated more accurate responses than Google Bard™ on patient-friendly prompting (p < 0.001). Google Bard™ responses were of a significantly lower grade level than ChatGPT for all prompts (p < 0.05). Despite eighth-grade prompting, response grade level for both chatbots was high: ChatGPT (10.5 ± 1.8) and Google Bard™ (9.6 ± 1.3). Prompting for references yielded 108/108 of chatbot-generated references. Forty-one (38.0%) citations were legitimate. Twenty (18.5%) provided accurately reported information from the reference. Conclusion: Although ChatGPT produced more accurate responses and at a higher education level than Google Bard™, both chatbots provided responses above recommended grade levels for patients and failed to provide accurate references.

The impact of astrocytic NF-κB on healthy and Alzheimer's disease brains.

Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)+-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated ß-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.

Evaluating ChatGPT Responses on Atrial Fibrillation for Patient Education.

Background ChatGPT is a language model that has gained widespread popularity for its fine-tuned conversational abilities. However, a known drawback to the artificial intelligence (AI) chatbot is its tendency to confidently present users with inaccurate information. We evaluated the quality of ChatGPT responses to questions pertaining to atrial fibrillation for patient education. Our analysis included the accuracy and estimated grade level of answers and whether references were provided for the answers. Methodology ChatGPT was prompted four times and 16 frequently asked questions on atrial fibrillation from the American Heart Association were asked. Prompts included Form 1 (no prompt), Form 2 (patient-friendly prompt), Form 3 (physician-level prompt), and Form 4 (prompting for statistics/references). Responses were scored as incorrect, partially correct, or correct with references (perfect). Flesch-Kincaid grade-level unique words and response lengths were recorded for answers. Proportions of the responses at differing scores were compared using the chi-square analysis. The relationship between form and grade level was assessed using the analysis of variance. Results Across all forms, scoring frequencies were one (1.6%) incorrect, five (7.8%) partially correct, 55 (85.9%) correct, and three (4.7%) perfect. Proportions of responses that were at least correct did not differ by form (p = 0.350), but perfect responses did (p = 0.001). Form 2 answers had a lower mean grade level (12.80 ± 3.38) than Forms 1 (14.23 ± 2.34), 3 (16.73 ± 2.65), and 4 (14.85 ± 2.76) (p < 0.05). Across all forms, references were provided in only three (4.7%) answers. Notably, when additionally prompted for sources or references, ChatGPT still only provided sources on three responses out of 16 (18.8%). Conclusions ChatGPT holds significant potential for enhancing patient education through accurate, adaptive responses. Its ability to alter response complexity based on user input, combined with high accuracy rates, supports its use as an informational resource in healthcare settings. Future advancements and continuous monitoring of AI capabilities will be crucial in maximizing the benefits while mitigating the risks associated with AI-driven patient education.

Evaluating ChatGPT-3.5 and ChatGPT-4.0 Responses on Hyperlipidemia for Patient Education.

Introduction Hyperlipidemia is prevalent worldwide and affects a significant number of US adults. It significantly contributes to ischemic heart disease and millions of deaths annually. With the increasing use of the internet for health information, tools like ChatGPT (OpenAI, San Francisco, CA, USA) have gained traction. ChatGPT version 4.0, launched in March 2023, offers enhanced features over its predecessor but requires a monthly fee. This study compares the accuracy, comprehensibility, and response length of the free and paid versions of ChatGPT for patient education on hyperlipidemia. Materials and methods ChatGPT versions 3.5 and 4.0 were prompted in three different ways and 25 questions from the Cleveland Clinic's frequently asked questions (FAQs) on hyperlipidemia. Prompts included no prompting (Form 1), patient-friendly prompting (Form 2), and physician-level prompting (Form 3). Responses were categorized as incorrect, partially correct, or correct. Additionally, the grade level and word count from each response were recorded for analysis. Results Overall, scoring frequencies for ChatGPT version 3.5 were: five (6.67%) incorrect, 18 partially correct (24%), and 52 (69.33%) correct. Scoring frequencies for ChatGPT version 4.0 were: one (1.33%) incorrect, 18 (24.00%) partially correct, and 56 (74.67%) correct. Correct answers did not significantly differ between ChatGPT version 3.5 and ChatGPT version 4.0 (p = 0.586). ChatGPT version 3.5 had a significantly higher grade reading level than version 4.0 (p = 0.0002). ChatGPT version 3.5 had a significantly higher word count than version 4.0 (p = 0.0073). Discussion There was no significant difference in accuracy between the free and paid versions of hyperlipidemia FAQs. Both versions provided accurate but sometimes partially complete responses. Version 4.0 offered more concise and readable information, aligning with the readability of most online medical resources despite exceeding the National Institutes of Health's (NIH's) recommended eighth-grade reading level. The paid version demonstrated superior adaptability in tailoring responses based on the input. Conclusion Both versions of ChatGPT provide reliable medical information, with the paid version offering more adaptable and readable responses. Healthcare providers can recommend ChatGPT as a source of patient education, regardless of the version used. Future research should explore diverse question formulations and ChatGPT's handling of incorrect information.

Unlocking Health Literacy: The Ultimate Guide to Hypertension Education From ChatGPT Versus Google Gemini.

Background Google Gemini (Google, Mountain View, CA) represents the latest advances in the realm of artificial intelligence (AI) and has garnered attention due to its capabilities similar to the increasingly popular ChatGPT (OpenAI, San Francisco, CA). Accurate dissemination of information on common conditions such as hypertension is critical for patient comprehension and management. Despite the ubiquity of AI, comparisons between ChatGPT and Gemini remain unexplored. Methods ChatGPT and Gemini were asked 52 questions derived from the American College of Cardiology's (ACC) frequently asked questions on hypertension, following a specified prompt. Prompts included: no prompting (Form 1), patient-friendly prompting (Form 2), physician-level prompting (Form 3), and prompting for statistics/references (Form 4). Responses were scored as incorrect, partially correct, or correct. Flesch-Kincaid (FK) grade level and word count were recorded. Results Across all forms, scoring frequencies were as follows: 23 (5.5%) incorrect, 162 (38.9%) partially correct, and 231 (55.5%) correct. ChatGPT showed higher rates of partially correct answers than Gemini (p = 0.0346). Physician-level prompts resulted in a higher word count across both platforms (p < 0.001). ChatGPT showed a higher FK grade level (p = 0.033) in physician-friendly prompting. Gemini exhibited a significantly higher mean word count (p < 0.001); however, ChatGPT had a higher FK grade level across all forms (p > 0.001). Conclusion To our knowledge, this study is the first to compare cardiology-related responses from ChatGPT and Gemini, two of the most popular AI chatbots. The grade level for most responses was collegiate level, which was above average for the National Institutes of Health (NIH) recommendations, but on par with most online medical information. Both chatbots responded with a high degree of accuracy, with inaccuracies being rare. Therefore, it is reasonable that cardiologists suggest either chatbot as a source of supplementary education.

Evaluating insomnia queries from an artificial intelligence chatbot for patient education.

STUDY OBJECTIVES: We evaluated the accuracy of ChatGPT in addressing insomnia-related queries for patient education and assessed ChatGPT's ability to provide varied responses based on differing prompting scenarios. METHODS: Four identical sets of 20 insomnia-related queries were posed to ChatGPT. Each set differed by the context in which ChatGPT was prompted: no prompt, patient-centered, physician-centered, and with references and statistics. Responses were reviewed by 2 academic sleep surgeons, 1 academic sleep medicine physician, and 2 sleep medicine fellows across 4 domains: clinical accuracy, prompt adherence, referencing, and statistical precision, using a binary grading system. Flesch-Kincaid grade-level scores were calculated to estimate the grade level of the responses, with statistical differences between prompts analyzed via analysis of variance and Tukey's test. Interrater reliability was calculated using Fleiss's kappa. RESULTS: The study revealed significant variations in the Flesch-Kincaid grade-level scores across 4 prompts: unprompted (13.2 ± 2.2), patient-centered (8.1 ± 1.9), physician-centered (15.4 ± 2.8), and with references and statistics (17.3 ± 2.3, P < .001). Despite poor Fleiss kappa scores, indicating low interrater reliability for clinical accuracy and relevance, all evaluators agreed that the majority of ChatGPT's responses were clinically accurate, with the highest variability on Form 4. The responses were also uniformly relevant to the given prompts (100% agreement). Eighty percent of the references ChatGPT cited were verified as both real and relevant, and only 25% of cited statistics were corroborated within referenced articles. CONCLUSIONS: ChatGPT can be used to generate clinically accurate responses to insomnia-related inquiries. CITATION: Alapati R, Campbell D, Molin N, et al. Evaluating insomnia queries from an artificial intelligence chatbot for patient education. J Clin Sleep Med. 2024;20(4):583-594.

Gene Therapy for Genetic Syndromes: Understanding the Current State to Guide Future Care.

Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, ß-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost-benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.

Evaluating ChatGPT Responses on Thyroid Nodules for Patient Education.

Background: ChatGPT, an artificial intelligence (AI) chatbot, is the fastest growing consumer application in history. Given recent trends identifying increasing patient use of Internet sources for self-education, we seek to evaluate the quality of ChatGPT-generated responses for patient education on thyroid nodules. Methods: ChatGPT was queried 4 times with 30 identical questions. Queries differed by initial chatbot prompting: no prompting, patient-friendly prompting, 8th-grade level prompting, and prompting for references. Answers were scored on a hierarchical score: incorrect, partially correct, correct, or correct with references. Proportions of responses at incremental score thresholds were compared by prompt type using chi-squared analysis. Flesch-Kincaid grade level was calculated for each answer. The relationship between prompt type and grade level was assessed using analysis of variance. References provided within ChatGPT answers were totaled and analyzed for veracity. Results: Across all prompts (n = 120 questions), 83 answers (69.2%) were at least correct. Proportions of responses that were at least partially correct (p = 0.795) and correct (p = 0.402) did not differ by prompt; responses that were correct with references did (p < 0.0001). Responses from 8th-grade level prompting were the lowest mean grade level (13.43 ± 2.86) and were significantly lower than no prompting (14.97 ± 2.01, p = 0.01) and prompting for references (16.43 ± 2.05, p < 0.0001). Prompting for references generated 80/80 (100%) of referenced medical publications within answers. Seventy references (87.5%) were legitimate citations, and 58/80 (72.5%) provided accurately reported information from the referenced publication. Conclusion: ChatGPT overall provides appropriate answers to most questions on thyroid nodules regardless of prompting. Despite targeted prompting strategies, ChatGPT reliably generates responses corresponding to grade levels well-above accepted recommendations for presenting medical information to patients. Significant rates of AI hallucination may preclude clinicians from recommending the current version of ChatGPT as an educational tool for patients at this time.

The mechanisms and roles of mitochondrial dynamics in C. elegans.

If mitochondria are the powerhouses of the cell, then mitochondrial dynamics are the power grid that regulates how that energy output is directed and maintained in response to unique physiological demands. Fission and fusion dynamics are highly regulated processes that fine-tune the mitochondrial networks of cells to enable appropriate responses to intrinsic and extrinsic stimuli, thereby maintaining cellular and organismal homeostasis. These dynamics shape many aspects of an organism's healthspan including development, longevity, stress resistance, immunity, and response to disease. In this review, we discuss the latest findings regarding the mechanisms and roles of mitochondrial dynamics by focussing on the nematode Caenorhabditis elegans. Whole live-animal studies in C. elegans have enabled a true organismal-level understanding of the impact that mitochondrial dynamics play in homeostasis over a lifetime.

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells.

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and TCR-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface MHC class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.

MDR1-EXPRESSING CD4+ T CELLS WITH TH1.17 FEATURES RESIST TO NEOADJUVANT CHEMOTHERAPY AND ARE ASSOCIATED WITH BREAST CANCER CLINICAL RESPONSE.

BACKGROUND: Multidrug resistance-1 (MDR1) transporter limits the intracellular accumulation of chemotherapies (paclitaxel, anthracyclines) used in breast cancer (BC) treatment. In addition to tumor cells, MDR1 is expressed on immune cell subsets in which it confers chemoresistance. Among human T cells, MDR1 is expressed by most CD8+ T cells, and a subset of CD4+ T helper (Th) cells. Here we explored the expression, function and regulation of MDR1 on CD4+ T cells and investigated the role of this population in response to neoadjuvant chemotherapy (NAC) in BC. METHODS: Phenotypic and functional characteristics of MDR1+ CD4 Th cells were assessed on blood from healthy donors and patients with BC by flow cytometry. These features were extended to CD4+ Th cells from untreated breast tumor by flow cytometry and RNA-sequencing (RNA-seq). We performed in vitro polarization assays to decipher MDR1 regulation on CD4 Th cells. We evaluated in vitro the impact of chemotherapy agents on MDR1+ CD4+ Th cells. We analyzed the impact of NAC treatment on MDR1+ CD4+ Th cells from blood and tumors and their association with treatment efficacy in two independent BC cohorts and in a public RNA-seq data set of BC tumor biopsies before and after NAC. Finally, we performed single cell (sc) RNAseq of blood CD4+ memory T cells from NAC-treated patients and combined them with an scRNAseq public data set. RESULTS: MDR1+ CD4 Th cells were strongly enriched in Th1.17 polyfunctional cells but also in Th17 cells, both in blood and untreated breast tumor tissues. Mechanistically, Tumor growth factor (TGF)-ß1 was required for MDR1 induction during in vitro Th17 or Th1.17 polarization. MDR1 expression conferred a selective advantage to Th1.17 and Th17 cells following paclitaxel treatment in vitro and in vivo in NAC-treated patients. scRNAseq demonstrated MDR1 association with tumor Th1.17 and Th with features of cytotoxic cells. Enrichment in MDR1+ CD4+ Th1.17 and Th17 cells, in blood and tumors positively correlated with pathological response. Absence of early modulation of Th1.17 and Th17 in NAC-resistant patients, argue for its use as a biomarker for chemotherapy regimen adjustment. CONCLUSION: MDR1 favored the enrichment of Th1.17 and Th17 in blood and tumor after NAC that correlated to clinical response.

Differences in Functional and Survival Outcomes Between Patients Receiving Primary Surgery vs Chemoradiation Therapy for Treatment of T1-T2 Oropharyngeal Squamous Cell Carcinoma.

Importance: Due to lack of data from high-powered randomized clinical trials, the differences in functional and survival outcomes for patients with oropharyngeal squamous cell carcinoma (OPSCC) undergoing primary transoral robotic surgery (TORS) vs primary radiation therapy and/or chemoradiation therapy (RT/CRT) are unclear. Objectives: To compare 5-year functional (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) and survivorship outcomes in patients with T1-T2 OPSCC receiving primary TORS vs RT/CRT. Design, Setting, and Population: This national multicenter cohort study used data from a global health network (TriNetX) to identify differences in functional and survival outcomes among patients with OPSCC who underwent primary TORS or RT/CRT in 2002 to 2022. After propensity matching, 726 patients with OPSCC met inclusion criteria. In the TORS group, 363 (50%) patients had undergone primary surgery, and in the RT/CRT group, 363 (50%) patients had received primary RT/CRT. Data analyses were performed from December 2022 to January 2023 using the TriNetX platform. Exposure: Primary surgery with TORS or primary treatment with radiation therapy and/or chemoradiation therapy. Main Outcomes and Measures: Propensity score matching was used to balance the 2 groups. Functional outcomes were measured at 6 months, 1 year, 3 years, 5 years, and more than 5 years posttreatment and included dysphagia, gastrostomy tube dependence, and tracheostomy dependence according to standard medical codes. Five-year overall survivorship was compared between patients undergoing primary TORS vs RT/CRT. Results: Propensity score matching allowed a study sample with 2 cohorts comprising statistically similar parameters with 363 (50%) patients in each. Patients in the TORS cohort had a mean (SD) age of 68.5 (9.9) vs 68.8 (9.7) years in RT/CRT cohort; 86% and 88% were White individuals, respectively; 79% of patients were men in both cohorts. Primary TORS was associated with clinically meaningful increased risk of dysphagia at 6 months (OR, 1.37; 95% CI, 1.01-1.84) and 1 year posttreatment (OR, 1.71; 95% CI, 1.22-2.39) compared with primary RT/CRT. Patients receiving surgery were less likely to be gastrostomy tube dependent at 6 months (OR, 0.46; 95% CI, 0.21-1.00) and 5 years posttreatment (risk difference, -0.05; 95% CI, -0.07 to -0.02). Differences in overall rates of tracheostomy dependence (OR, 0.97; 95% CI, 0.51-1.82) between groups were not clinically meaningful. Patients with OPSCC, unmatched for cancer stage or human papillomavirus status, who received RT/CRT had worse 5-year overall survival than those who underwent primary surgery (70.2% vs 58.4%; hazard ratio, 0.56; 95% CI, 0.40-0.79). Conclusions and Relevance: This national multicenter cohort study of patients undergoing primary TORS vs primary RT/CRT for T1-T2 OPSCC found that primary TORS was associated with a clinically meaningful increased risk of short-term dysphagia. Patients treated with primary RT/CRT had an increased risk of short- and long-term gastrostomy tube dependence and worse 5-year overall survival than those who underwent surgery.

Evaluating ChatGPT responses on obstructive sleep apnea for patient education.

STUDY OBJECTIVES: We evaluated the quality of ChatGPT responses to questions on obstructive sleep apnea for patient education and assessed how prompting the chatbot influences correctness, estimated grade level, and references of answers. METHODS: ChatGPT was queried 4 times with 24 identical questions. Queries differed by initial prompting: no prompting, patient-friendly prompting, physician-level prompting, and prompting for statistics/references. Answers were scored on a hierarchical scale: incorrect, partially correct, correct, correct with either statistic or referenced citation ("correct+"), or correct with both a statistic and citation ("perfect"). Flesch-Kincaid grade level and citation publication years were recorded for answers. Proportions of responses at incremental score thresholds were compared by prompt type using chi-squared analysis. The relationship between prompt type and grade level was assessed using analysis of variance. RESULTS: Across all prompts (n = 96 questions), 69 answers (71.9%) were at least correct. Proportions of responses that were at least partially correct (P = .387) or correct (P = .453) did not differ by prompt; responses that were at least correct+ (P < .001) or perfect (P < .001) did. Statistics/references prompting provided 74/77 (96.1%) references. Responses from patient-friendly prompting had a lower mean grade level (12.45 ± 2.32) than no prompting (14.15 ± 1.59), physician-level prompting (14.27 ± 2.09), and statistics/references prompting (15.00 ± 2.26) (P < .0001). CONCLUSIONS: ChatGPT overall provides appropriate answers to most questions on obstructive sleep apnea regardless of prompting. While prompting decreases response grade level, all responses remained above accepted recommendations for presenting medical information to patients. Given ChatGPT's rapid implementation, sleep experts may seek to further scrutinize its medical literacy and utility for patients. CITATION: Campbell DJ, Estephan LE, Mastrolonardo EV, Amin DR, Huntley CT, Boon MS. Evaluating ChatGPT responses on obstructive sleep apnea for patient education. J Clin Sleep Med. 2023;19(12):1989-1995.