neuroGPT-X: toward a clinic-ready large language model.

OBJECTIVE: The objective was to assess the performance of a context-enriched large language model (LLM) compared with international neurosurgical experts on questions related to the management of vestibular schwannoma. Furthermore, another objective was to develop a chat-based platform incorporating in-text citations, references, and memory to enable accurate, relevant, and reliable information in real time. METHODS: The analysis involved 1) creating a data set through web scraping, 2) developing a chat-based platform called neuroGPT-X, 3) enlisting 8 expert neurosurgeons across international centers to independently create questions (n = 1) and to answer (n = 4) and evaluate responses (n = 3) while blinded, and 4) analyzing the evaluation results on the management of vestibular schwannoma. In the blinded phase, all answers were assessed for accuracy, coherence, relevance, thoroughness, speed, and overall rating. All experts were unblinded and provided their thoughts on the utility and limitations of the tool. In the unblinded phase, all neurosurgeons provided answers to a Likert scale survey and long-answer questions regarding the clinical utility, likelihood of use, and limitations of the tool. The tool was then evaluated on the basis of a set of 103 consensus statements on vestibular schwannoma care from the 8th Quadrennial International Conference on Vestibular Schwannoma. RESULTS: Responses from the naive and context-enriched Generative Pretrained Transformer (GPT) models were consistently rated not significantly different in terms of accuracy, coherence, relevance, thoroughness, and overall performance, and they were often rated significantly higher than expert responses. Both the naive and content-enriched GPT models provided faster responses to the standardized question set than expert neurosurgeon respondents (p < 0.01). The context-enriched GPT model agreed with 98 of the 103 (95%) consensus statements. Of interest, all expert surgeons expressed concerns about the reliability of GPT in accurately addressing the nuances and controversies surrounding the management of vestibular schwannoma. Furthermore, the authors developed neuroGPT-X, a chat-based platform designed to provide point-of-care clinical support and mitigate the limitations of human memory. neuroGPT-X incorporates features such as in-text citations and references to enable accurate, relevant, and reliable information in real time. CONCLUSIONS: The present study, with its subspecialist-level performance in generating written responses to complex neurosurgical problems for which evidence-based consensus for management is lacking, suggests that context-enriched LLMs show promise as a point-of-care medical resource. The authors anticipate that this work will be a springboard for expansion into more medical specialties, incorporating evidence-based clinical information and developing expert-level dialogue surrounding LLMs in healthcare.

Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Mechanisms and clinical implications in renal carcinoma resistance: narrative review of immune checkpoint inhibitors.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma. The prognosis for patients with ccRCC has improved over recent years with the use of combination therapies with an anti-programmed death-1 (PD-1) backbone. This has enhanced the quality of life and life expectancy of patients with this disease. Unfortunately, not all patients benefit; eventually, most patients will develop resistance to therapy and progress. Recent molecular, biochemical, and immunological research has extensively researched anti-angiogenic and immune-based treatment resistance mechanisms. This analysis offers an overview of the principles underpinning the resistance pathways related to immune checkpoint inhibitors (ICIs). Additionally, novel approaches to overcome resistance that may be considered for the trial context are discussed.

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells.

Background: Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of MAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. Methods: We studied deletion of Adipsin, and its downstream effector, C3, in C57BL/6 mice as well as the bone-protected PPARγ constitutive deacetylation 2KR mice to assess BM plasticity. The mice were challenged with thiazolidinedione treatment, calorie restriction, or aging to induce bone loss and MAT expansion. Analysis of bone mineral density and marrow adiposity was performed using a µCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high-calorie diet in healthy human volunteers. Results: We show that Adipsin is the most upregulated adipokine during MAT expansion in mice and humans in a PPARγ acetylation-dependent manner. Genetic ablation of Adipsin in mice specifically inhibited MAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/ß-catenin signaling. Conclusions: Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. Funding: This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), R24DK092759 (CJR), and P01HL087123 (LQ).

Human bone perivascular niche-on-a-chip for studying metastatic colonization.

Eight out of 10 breast cancer patients die within 5 years after the primary tumor has spread to the bones. Tumor cells disseminated from the breast roam the vasculature, colonizing perivascular niches around blood capillaries. Slow flows support the niche maintenance by driving the oxygen, nutrients, and signaling factors from the blood into the interstitial tissue, while extracellular matrix, endothelial cells, and mesenchymal stem cells regulate metastatic homing. Here, we show the feasibility of developing a perfused bone perivascular niche-on-a-chip to investigate the progression and drug resistance of breast cancer cells colonizing the bone. The model is a functional human triculture with stable vascular networks within a 3D native bone matrix cultured on a microfluidic chip. Providing the niche-on-a-chip with controlled flow velocities, shear stresses, and oxygen gradients, we established a long-lasting, self-assembled vascular network without supplementation of angiogenic factors. We further show that human bone marrow-derived mesenchymal stem cells, which have undergone phenotypical transition toward perivascular cell lineages, support the formation of capillary-like structures lining the vascular lumen. Finally, breast cancer cells exposed to interstitial flow within the bone perivascular niche-on-a-chip persist in a slow-proliferative state associated with increased drug resistance. We propose that the bone perivascular niche-on-a-chip with interstitial flow promotes the formation of stable vasculature and mediates cancer cell colonization.

Development of a research-oriented system for collecting mechanical ventilator waveform data.

Lack of access to high-frequency, high-volume patient-derived data, such as mechanical ventilator waveform data, has limited the secondary use of these data for research, quality improvement, and decision support. Existing methods for collecting these data are obtrusive, require high levels of technical expertise, and are often cost-prohibitive, limiting their use and scalability for research applications. We describe here the development of an unobtrusive, open-source, scalable, and user-friendly architecture for collecting, transmitting, and storing mechanical ventilator waveform data that is generalizable to other patient care devices. The system implements a software framework that automates and enforces end-to-end data collection and transmission. A web-based data management application facilitates nontechnical end users' abilities to manage data acquisition devices, mitigates data loss and misattribution, and automates data storage. Using this integrated system, we have been able to collect ventilator waveform data from >450 patients as part of an ongoing clinical study.

Ectopic implantation of juvenile osteochondral tissues recapitulates endochondral ossification.

Subcutaneous implantation in a mouse can be used to investigate tissue maturation in vivo. Here we demonstrate that this simple model can recapitulate endochondral ossification associated with native skeletal development. By histological and micro-computed tomography analysis we investigated morphological changes of immature bovine osteochondral tissues over the course of subcutaneous implantation in immunocompromised mice for up to 10 weeks. We observed multiple similarities between the ectopic process and native endochondral ossification: (i) permanent cartilage retention in the upper zones; (ii) progressive loss of transient cartilage accompanied by bone formation at the interface; and (iii) remodelling of nascent endochondral bone into mature cancellous bone. Importantly, these processes were mediated by osteoclastogenesis and vascularization. Taken together, these findings advance our understanding of how the simple ectopic model can be used to study phenotypic changes associated with endochondral ossification of native and engineered osteochondral tissues in vivo.

Development and Validation of a Multi-Algorithm Analytic Platform to Detect Off-Target Mechanical Ventilation.

Healthcare-specific analytic software is needed to process the large volumes of streaming physiologic waveform data increasingly available from life support devices such as mechanical ventilators. Detection of clinically relevant events from these data streams will advance understanding of critical illness, enable real-time clinical decision support, and improve both clinical outcomes and patient experience. We used mechanical ventilation waveform data (VWD) as a use case to address broader issues of data access and analysis including discrimination between true events and waveform artifacts. We developed an open source data acquisition platform to acquire VWD, and a modular, multi-algorithm analytic platform (ventMAP) to enable automated detection of off-target ventilation (OTV) delivery in critically-ill patients. We tested the hypothesis that use of artifact correction logic would improve the specificity of clinical event detection without compromising sensitivity. We showed that ventMAP could accurately detect harmful forms of OTV including excessive tidal volumes and common forms of patient-ventilator asynchrony, and that artifact correction significantly improved the specificity of event detection without decreasing sensitivity. Our multi-disciplinary approach has enabled automated analysis of high-volume streaming patient waveform data for clinical and translational research, and will advance the study and management of critically ill patients requiring mechanical ventilation.

Blocking FSH induces thermogenic adipose tissue and reduces body fat.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.

Spine Trabecular Bone Score as an Indicator of Bone Microarchitecture at the Peripheral Skeleton in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Studies using high-resolution peripheral quantitative computed tomography showed progressive abnormalities in cortical and trabecular microarchitecture and biomechanical competence over the first year after kidney transplantation. However, high-resolution peripheral computed tomography is a research tool lacking wide availability. In contrast, the trabecular bone score is a novel and widely available tool that uses gray-scale variograms of the spine image from dual-energy x-ray absorptiometry to assess trabecular quality. There are no studies assessing whether trabecular bone score characterizes bone quality in kidney transplant recipients. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Between 2009 and 2010, we conducted a study to assess changes in peripheral skeletal microarchitecture, measured by high-resolution peripheral computed tomography, during the first year after transplantation in 47 patients managed with early corticosteroid-withdrawal immunosuppression. All adult first-time transplant candidates were eligible. Patients underwent imaging with high-resolution peripheral computed tomography and dual-energy x-ray absorptiometry pretransplantation and 3, 6, and 12 months post-transplantation. We now test if, during the first year after transplantation, trabecular bone score assesses the evolution of bone microarchitecture and biomechanical competence as determined by high-resolution peripheral computed tomography. RESULTS: At baseline and follow-up, among the 72% and 78%, respectively, of patients having normal bone mineral density by dual-energy x-ray absorptiometry, 53% and 50%, respectively, were classified by trabecular bone score as having high fracture risk. At baseline, trabecular bone score correlated with spine, hip, and ultradistal radius bone mineral density by dual-energy x-ray absorptiometry and cortical area, density, thickness, and porosity; trabecular density, thickness, separation, and heterogeneity; and stiffness and failure load by high-resolution peripheral computed tomography. Longitudinally, each percentage increase in trabecular bone score was associated with increases in trabecular number (0.35%±1.4%); decreases in trabecular thickness (-0.45%±0.15%), separation (-0.40%±0.15%), and network heterogeneity (-0.48%±0.20%); and increases in failure load (0.22%±0.09%) by high-resolution peripheral computed tomography (all P<0.05). CONCLUSIONS: Trabecular bone score may be a useful method to assess and monitor bone quality and strength and classify fracture risk in kidney transplant recipients.

Extracellular matrix components and culture regimen selectively regulate cartilage formation by self-assembling human mesenchymal stem cells in vitro and in vivo.

BACKGROUND: Cartilage formation from self-assembling mesenchymal stem cells (MSCs) in vitro recapitulate important cellular events during mesenchymal condensation that precedes native cartilage development. The goal of this study was to investigate the effects of cartilaginous extracellular matrix (ECM) components and culture regimen on cartilage formation by self-assembling human MSCs in vitro and in vivo. METHODS: Human bone marrow-derived MSCs (hMSCs) were seeded and compacted in 6.5-mm-diameter transwell inserts with coated (type I, type II collagen) or uncoated (vehicle) membranes, at different densities (0.5 × 106, 1.0 × 106, 1.5 × 106 per insert). Pellets were formed by aggregating hMSCs (0.25 × 106) in round-bottomed wells. All tissues were cultured for up to 6 weeks for in vitro analyses. Discs (cultured for 6, 8 or 10 weeks) and pellets (cultured for 10 weeks) were implanted subcutaneously in immunocompromised mice to evaluate the cartilage stability in vivo. RESULTS: Type I and type II collagen coatings enabled cartilage disc formation from self-assembling hMSCs. Without ECM coating, hMSCs formed dome-shaped tissues resembling the pellets. Type I collagen, expressed in the prechondrogenic mesenchyme, improved early chondrogenesis versus type II collagen. High seeding density improved cartilage tissue properties but resulted in a lower yield of disc formation. Discs and pellets exhibited compositional and organizational differences in vitro and in vivo. Prolonged chondrogenic induction of the discs in vitro expedited endochondral ossification in vivo. CONCLUSIONS: The outcomes of cartilage tissues formed from self-assembling MSCs in vitro and in vivo can be modulated by the control of culture parameters. These insights could motivate new directions for engineering cartilage and bone via a cartilage template from self-assembling MSCs.