Citations

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 ( ITPR1 ), 2 ( ITPR2 ), and 3 ( ITPR3 ) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant—NM_002224.3:c.7570C>T, p.Arg2524Cys—causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4 + lymphopenia, a quasi-absence of naïve CD4 + and CD8 + cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg 2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Abstract The significance of anterior cruciate ligament (ACL) remnants during reconstruction remains unclear. Co‐culturing ACL remnant cells and bone marrow stromal cells (BMSCs) may reduce apoptosis and enhance hamstring tendon activity. This study investigated whether extracellular vesicles (EVs), which facilitate cell–cell interactions, act as the active components, improving graft maturation in this co‐culture. The effects of EVs on cell viability, proliferation, migration and gene expression in the rabbit ACL remnant cells and BMSCs were assessed using control (BMSC‐only culture), co‐culture (ACL remnant cells and BMSCs, CM) and co‐culture without EVs (CM ∆ EVs) media. EVs were isolated from control (BMSC‐EV) and co‐culture (CM‐EV) media and characterized. CM significantly enhanced the proliferation, migration and expression of transforming growth factor ( TGF‐β )‐, vascular endothelial growth factor ( VEGF )‐, collagen synthesis‐ and tenogenesis‐related genes. However, CM‐induced effects were reversed by the CM ∆ EVs treatment. CM‐EV treatment exhibited higher potential to enhance proliferation, migration and gene expression in the ACL remnant cells and BMSCs than BMSC‐EV and non‐EV treatments. In conclusion, EVs, secreted under the coexistence of ACL remnant cells and BMSCs, primarily increase the cell viability, proliferation, migration and gene expression of collagen synthesis‐, TGF‐β ‐, VEGF ‐ and tenogenesis‐related genes in both cell types.

Background Professional opinion polling has become a popular means of seeking advice for complex nephrology questions in the #AskRenal community on X. ChatGPT is a large language model with remarkable problem-solving capabilities, but its ability to provide solutions for real-world clinical scenarios remains unproven. This study seeks to evaluate how closely ChatGPT's responses align with current prevailing medical opinions in nephrology. Methods Nephrology polls from X were submitted to ChatGPT-4, which generated answers without prior knowledge of the poll outcomes. Its responses were compared to the poll results (inter-rater) and a second set of responses given after a one-week interval (intra-rater) using Cohen's kappa statistic (κ). Subgroup analysis was performed based on question subject matter. Results Our analysis comprised two rounds of testing ChatGPT on 271 nephrology-related questions. In the first round, ChatGPT's responses agreed with poll results for 163 of the 271 questions (60.2%; κ = 0.42, 95% CI: 0.38–0.46). In the second round, conducted to assess reproducibility, agreement improved slightly to 171 out of 271 questions (63.1%; κ = 0.46, 95% CI: 0.42–0.50). Comparison of ChatGPT's responses between the two rounds demonstrated high internal consistency, with agreement in 245 out of 271 responses (90.4%; κ = 0.86, 95% CI: 0.82–0.90). Subgroup analysis revealed stronger performance in the combined areas of homeostasis, nephrolithiasis, and pharmacology (κ = 0.53, 95% CI: 0.47–0.59 in both rounds), compared to other nephrology subfields. Conclusion ChatGPT-4 demonstrates modest capability in replicating prevailing professional opinion in nephrology polls overall, with varying performance levels between question topics and excellent internal consistency. This study provides insights into the potential and limitations of using ChatGPT in medical decision making.

AbstractIron Dextran is a widely used iron oxide compound to treat iron‐deficiency anemia patients in the clinic. Similar to other iron oxide compounds such as Ferumoxytol, it can also be used off‐label as an intravascular magnetic resonance imaging (MRI) contrast agent due to its strong iron‐induced T2 and T2* shortening effects. In this study, we seek to evaluate the feasibility of using Iron Dextran enhanced multi‐echo susceptibility weighted imaging (SWI) MRI at 7T to image arterial and venous blood vessels in the human brain. Phantom experiments were performed to measure the r2* relaxivity for Iron Dextran in blood, based on which the SWI sequence was optimized. Pre‐ and post‐infusion MR images were acquired in human subjects from which maps of arteries and veins were extracted. The post‐contrast SWI images showed enhanced susceptibility difference between blood and the surrounding tissue in both arteries and veins. Our results showed that the proposed Iron Dextran enhanced multi‐echo SWI approach allowed the visualization of blood vessels with diameters down to ~100 μm, including small blood vessels supplying and draining small brain structures such as the hippocampus. We conclude that Iron Dextran can be an alternative iron‐based MRI contrast agent for blood vessel imaging in the human brain.

Chronic kidney disease (CKD) patients can benefit from personalized education on lifestyle and nutrition management strategies to enhance healthcare outcomes. The potential use of chatbots, introduced in 2022, as a tool for educating CKD patients has been explored. A set of 15 questions on lifestyle modification and nutrition, derived from a thorough review of three specific KDIGO guidelines, were developed and posed in various formats, including original, paraphrased with different adverbs, incomplete sentences, and misspellings. Four versions of AI were used to answer these questions: ChatGPT 3.5 (March and September 2023 versions), ChatGPT 4, and Bard AI. Additionally, 20 questions on lifestyle modification and nutrition were derived from the NKF KDOQI guidelines for nutrition in CKD (2020 Update) and answered by four versions of chatbots. Nephrologists reviewed all answers for accuracy. ChatGPT 3.5 produced largely accurate responses across the different question complexities, with occasional misleading statements from the March version. The September 2023 version frequently cited its last update as September 2021 and did not provide specific references, while the November 2023 version did not provide any misleading information. ChatGPT 4 presented answers similar to 3.5 but with improved reference citations, though not always directly relevant. Bard AI, while largely accurate with pictorial representation at times, occasionally produced misleading statements and had inconsistent reference quality, although an improvement was noted over time. Bing AI from November 2023 had short answers without detailed elaboration and sometimes just answered “YES”. Chatbots demonstrate potential as personalized educational tools for CKD that utilize layman’s terms, deliver timely and rapid responses in multiple languages, and offer a conversational pattern advantageous for patient engagement. Despite improvements observed from March to November 2023, some answers remained potentially misleading. ChatGPT 4 offers some advantages over 3.5, although the differences are limited. Collaboration between healthcare professionals and AI developers is essential to improve healthcare delivery and ensure the safe incorporation of chatbots into patient care.

Abstract Generative artificial intelligence (AI) holds immense potential for medical applications, but the lack of a comprehensive evaluation framework and methodological deficiencies in existing studies hinder its effective implementation. Standardized assessment guidelines are crucial for ensuring reliable and consistent evaluation of generative AI in healthcare. Our objective is to develop robust, standardized guidelines tailored for evaluating generative AI performance in medical contexts. Through a rigorous literature review utilizing the Web of Sciences, Cochrane Library, PubMed, and Google Scholar, we focused on research testing generative AI capabilities in medicine. Our multidisciplinary team of experts conducted discussion sessions to develop a comprehensive 32‐item checklist. This checklist encompasses critical evaluation aspects of generative AI in medical applications, addressing key dimensions such as question collection, querying methodologies, and assessment techniques. The checklist and its broader assessment framework provide a holistic evaluation of AI systems, delineating a clear pathway from question gathering to result assessment. It guides researchers through potential challenges and pitfalls, enhancing research quality and reporting and aiding the evolution of generative AI in medicine and life sciences. Our framework furnishes a standardized, systematic approach for testing generative AI's applicability in medicine. For a concise checklist, please refer to Table S or visit GenAIMed.org .

AbstractTargeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long‐established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC‐independent. Mechanistically, UK5099 abrogates mitochondria‐NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL‐1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3‐driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.

PURPOSE Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor–positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor–positive, human epidermal growth factor receptor 2–negative BC after adjuvant/neoadjuvant chemotherapy. METHODS Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor–positive BC. RESULTS One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Background: Despite the prevalence and incidence of kidney stones progressively increasing worldwide, public awareness of this condition remains unclear. Understanding trends of awareness can assist healthcare professionals and policymakers in planning and implementing targeted health interventions. This study investigated online search interest in “kidney stone” by analyzing Google Trends, focusing on stationarity of the trends and predicting future trends. Methods: We performed time series analysis on worldwide Google monthly search data from January 2004 to November 2023. The Augmented Dickey–Fuller (ADF) test was used to assess the stationarity of the data, with a p-value below 0.05 indicating stationarity. Time series forecasting was performed using the autoregressive integrated moving average to predict future trends. Results: The highest search interest for “kidney stone” (score 100) was in August 2022, while the lowest was in December 2007 (score 36). As of November 2023, search interest remained high, at 92. The ADF test was significant (p = 0.023), confirming data stationarity. The time series forecasting projected continued high public interest, likely reflecting ongoing concern and awareness. Notably, diverse regions such as Iran, the Philippines, Ecuador, the United States, and Nepal showed significant interest, suggesting widespread awareness of nephrolithiasis. Conclusion: This study highlighted that “kidney stone” is a consistently relevant health issue globally. The increase and stationarity of search trends, the forecasted sustained interest, and diverse regional interest emphasize the need for collaborative research and educational initiatives. This study’s analysis serves as a valuable tool for shaping future healthcare policies and research directions in addressing nephrolithiasis related health challenges.