Low serum Metrnl levels are associated with increased risk of sarcopenia in the older adults.

PURPOSE: Sarcopenia is a geriatric syndrome characterized by progressive loss of muscle mass and function. Meteorin-like (Metrnl) is a secretory protein that has protective effects on skeletal muscle injury. However, the association of Metrnl level with sarcopenia remains unclear. METHODS: A total of 772 community-dwelling older adults (median age = 76 years), comprising 409 males and 363 females, from both urban and rural areas were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. Appendicular skeletal muscle mass index (ASMI), grip strength, and gait speed were measured for the assessment of sarcopenia. RESULTS: We found that serum Metrnl levels were lower in patients with sarcopenia [median (IQR) = 180.1 (151.3-220.3) pg/mL] than older adults without sarcopenia [211.9 (163.2-270.0) pg/mL, P < 0.001]. Receiver-operating characteristic curve analysis showed that the optimal cut-off value of serum Metrnl level that predicted sarcopenia was 197.2 pg/mL with a sensitivity of 59.2% and a specificity of 63.8% (AUC = 0.63, 95% CI = 0.59-0.67, P < 0.001). Multivariate logistic regression analyses showed that lower serum Metrnl level (< 197.2 pg/mL) was significantly associated with increased risk of sarcopenia (adjusted OR = 2.358, 2.36, 95% CI = 1.528-3.685, P < 0.001). Moreover, serum Metrnl concentration was positively correlated with the components of sarcopenia including ASMI (r = 0.135, P < 0.001), grip strength (r = 0.102, P = 0.005), and gait speed (r = 0.106, P = 0.003). CONCLUSIONS: Taken together, our findings demonstrate that low serum Metrnl level is correlated with increased risk of sarcopenia in the older adults.

Visual reading for [18F]Florzolotau Tau PET scans in progressive supranuclear palsy.

PURPOSE: The identification of tau accumulation within living brains holds significant potential in facilitating accurate diagnosis of progressive supranuclear palsy (PSP). While visual assessment is frequently employed, standardized methods for tau positron emission tomography (PET) specifically in PSP are absent. We aimed to develop a visual reading algorithm dedicated to the evaluation of [18F]Florzolotau PET in PSP. METHODS: 148 PSP and 30 healthy volunteers were divided into a development set (for the establishment of the reading rules; n = 89) and a testing set (for the validation of the reading rules; n = 89). For differential diagnosis, 55 α-synucleinopathies were additionally included into the testing set. The visual reading method was established by an experienced assessor (Reader 0) and was then validated by Reader 0 and two additional readers on regional and overall binary manners. A positive binding in both midbrain and globus pallidus/putamen regions was characterized as a PSP-like pattern, whereas any other pattern was classified as non-PSP-like. RESULTS: Reader 1 (94.4%) and Reader 2 (93.8%) showed excellent agreement for the overall binary determination against Reader 0. The regional binary determinations of midbrain and globus pallidus/putamen showed excellent agreement among readers (kappa > 0.80). The overall binary evaluation demonstrated reproducibility of 86.1%, 94.4% and 77.8% for three readers. The visual reading algorithm showed high agreement with regional standardized uptake value ratios and clinical diagnoses. CONCLUSION: Through the application of the suggested visual reading algorithm, [18F]Florzorotau PET imaging demonstrated a robust performance for the imaging diagnosis of PSP.

A bibliometric analysis of respiratory mechanics research related to acute respiratory distress syndrome from 1985 to 2023.

Background: Acute respiratory distress syndrome (ARDS) is a severe condition characterized by lung stiffness and compromised gas exchange, often requiring mechanical ventilation for treatment. In addition to its clinical significance, understanding the publication trends and research patterns in respiratory mechanics related to ARDS can provide insights into the evolution of this field from a bibliometric perspective, aiding in strategic planning and resource allocation for future research endeavors. Objective: This study aimed to explore the trends and identify the hotspots in respiratory mechanics research related to ARDS. Methods: All relevant studies on respiratory mechanics of ARDS published between 1985 and 2023 were retrieved from the Web of Science Core Collection (WoSCC), and the retrieval strategy was topic search "TS = respiratory mechanics OR lung mechanics AND TS = ARDS OR acute respiratory distress syndrome." Annual trends, citation patterns, and contributions from countries, institutions, authors, and journals were analyzed using Bibliometrix Biblioshiny. Networks and overlay of authors, institutions, countries, journals, co-citations, and keywords were analyzed and visualized using VOSviewer. Results: Our analysis included 1,248 articles published between 1985 and 2023, revealing fluctuations in publication output over time. The United States emerged as the leading contributor, with Critical Care Medicine being the most prominent journal. Key research themes included mechanical ventilation, acute lung injury, and protective ventilation strategies. International collaboration was evident, facilitating knowledge exchange and interdisciplinary cooperation. Conclusion: Our study sheds light on the evolving landscape of respiratory mechanics research in ARDS. International collaboration is pivotal in advancing the field, while researchers increasingly focus on personalized approaches to address the complexities of ARDS respiratory mechanics.

Molecular targets and strategies in the development of nucleic acid cancer vaccines: from shared to personalized antigens.

Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.

Comparative transcriptome analysis and identification of candidate bZIP transcription factors involved in anthraquinone biosynthesis in Rheum officinale Baill.

Rhubarb is a traditional medicinal plant in China, whose pharmacological effects derive mainly from its anthraquinones. However, the regulatory mechanism affecting anthraquinone biosynthesis in R. officinale remains poorly understood. We assembled a high-quality, full-length transcriptome using single-molecule real-time (SMRT) sequencing. 274 unigenes potentially involved in the biosynthesis of anthraquinones, including those in the shikimate, polyketide, MVA and MEP pathways, were identified based on full-length transcriptome. Differentially expressed genes (DEGs) induced by MeJA treatment and DEGs between different tissues were identified through next-generation sequencing (NGS), revealing the genes that may be involved in the biosynthesis of anthraquinones. The basic leucine zipper (bZIP) transcription factors of R. officinale were systematically identified. Key genes such as RobZIP50 and RobZIP53 were systematically identified and found to be associated with anthraquinone biosynthesis in R. officinale through differential expression, co-expression and protein interaction analyses. RobZIP50 and RobZIP53 were highly expressed in roots and rhizomes, and significantly increased after 12 h of MeJA treatment. Additionally, both RobZIP50 and RobZIP53 were localized exclusively in the nucleus, with RobZIP53 showing significant transcriptional activity. Taken together, our results suggest that RobZIP53 may play a role in regulating anthraquinone biosynthesis in R. officinale.

The efficacy of socially assistive robots in improving children's pain and negative affectivity during needle-based invasive treatment: A systematic review and meta-analysis.

BACKGROUND: The ability of socially assistive robots (SARs) to treat dementia and Alzheimer's disease has been verified. Currently, to increase the range of their application, there is an increasing amount of interest in using SARs to relieve pain and negative emotions among children in routine medical settings. However, there is little consensus regarding the use of these robots. OBJECTIVE: This study aimed to evaluate the effect of SARs on pain and negative affectivity among children undergoing invasive needle-based procedures. DESIGN: This study was a systematic review and meta-analysis of randomized controlled trials that was conducted in accordance with the Cochrane Handbook guidelines. METHODS: The PubMed, CINAHL, Web of Science, Cochrane Library, Embase, CNKI, and WanFang databases were searched from inception to January 2024 to identify relevant randomized controlled trials (RCTs). We used the Cochrane Risk of Bias tool 2.0 (RoB2.0) to assess the risk of bias among the included studies, and we used RevMan 5.4 software to conduct the meta-analysis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess the quality of the evidence. RESULTS: Ten RCTs involving 815 pediatric subjects were selected for this review and reported outcomes related to pain and emotions during IV placement, port needle insertion, flu vaccination, blood sampling, and dental treatment. Children undergoing needle-related procedures with SARs reported less anxiety (SMD= -0.36; 95% CI= -0.64, -0.09) and fewer distressed avoidance behaviors (SMD= -0.67; 95% CI= -1.04, -0.30) than did those receiving typical care. There were nonsignificant differences between these groups in terms of in pain (SMD = -0.02; 95% CI = - 0.81, 0.78) and fear (SMD = 0.38; 95% CI= -0.06, 0.82). The results of exploratory subgroup analyses revealed no statistically significant differences based on the intervention type of robots or anesthetic use. CONCLUSIONS: The use of SARs is a promising intervention method for alleviating anxiety and distress among children undergoing needle-related procedures. However, additional high-quality randomized controlled trials are needed to further validate these conclusions. TRIAL REGISTRATION: The protocol of this study has been registered in the database PROSPERO (registration ID: CRD42023413279).

A natural language processing system for the efficient extraction of cell markers.

Single-cell RNA sequencing (scRNA-seq) has emerged as a pivotal tool for exploring cellular landscapes across diverse species and tissues. Precise annotation of cell types is essential for understanding these landscapes, relying heavily on empirical knowledge and curated cell marker databases. In this study, we introduce MarkerGeneBERT, a natural language processing (NLP) system designed to extract critical information from the literature regarding species, tissues, cell types, and cell marker genes in the context of single-cell sequencing studies. Leveraging MarkerGeneBERT, we systematically parsed full-text articles from 3702 single-cell sequencing-related studies, yielding a comprehensive collection of 7901 cell markers representing 1606 cell types across 425 human tissues/subtissues, and 8223 cell markers representing 1674 cell types across 482 mouse tissues/subtissues. Comparative analysis against manually curated databases demonstrated that our approach achieved 76% completeness and 75% accuracy, while also unveiling 89 cell types and 183 marker genes absent from existing databases. Furthermore, we successfully applied the compiled brain tissue marker gene list from MarkerGeneBERT to annotate scRNA-seq data, yielding results consistent with original studies. Conclusions: Our findings underscore the efficacy of NLP-based methods in expediting and augmenting the annotation and interpretation of scRNA-seq data, providing a systematic demonstration of the transformative potential of this approach. The 27323 manual reviewed sentences for training MarkerGeneBERT and the source code are hosted at https://github.com/chengpeng1116/MarkerGeneBERT .

Screening for the presence of aberrantly expressed ACTR2 in osteosarcoma and analyzing its mechanism of action through an online database.

Osteosarcoma (OS) represents the most prevalent malignant bone tumor clinically, significantly impacting the health and safety of patients. The exploration of molecular pathogenic mechanisms is deemed a breakthrough for OS diagnosis and treatment. Within the GSE16088 dataset, a total of 1,948 differentially expressed genes (DEGs) were identified, comprising 1,697 down-regulated and 251 up-regulated genes. Notably, only two DEGs were associated with the response to trichostatin A: ARP2 actin-related protein 2 homolog (ACTR2) and MEF2C; ACTR2 garnered particular interest. Subsequently, 57 OS patients (research group) and 50 healthy controls from the same period (control group) were selected for analysis. The expression of ACTR2 in peripheral blood in both groups, as well as its levels in cancerous tissues and adjacent counterparts of OS patients, were evaluated, ascertaining the correlation between ACTR2 and OS. OS cases exhibited lower levels of ACTR2 compared to controls (P<0.05), with ACTR2 expression demonstrating a robust diagnostic capability for OS. Similarly, ACTR2 expression was diminished in cancer tissues (P<0.05). A three-year prognostic follow-up was conducted to assess the prognostic value of ACTR2 in OS patients. The follow-up findings revealed a significantly lower survival rate among patients with low ACTR2 expression in contrast to those with high expression (P<0.05). In vitro studies involved the construction of abnormal expression vectors for ACTR2 and miR-374a-5p, which were transfected into human OS cells (U2OS, SAOS). The outcomes indicated that elevating ACTR2 or suppressing miR-374a-5p attenuated the proliferative, invasive, and migratory capacities as well as the epithelial-mesenchymal transition (EMT) of OS cells while enhancing their apoptosis. Conversely, upregulation of miR-374a-5p yielded opposing effects (P<0.05). The dual-luciferase reporter (DLR) assay demonstrated that the fluorescence activity of ACTR2-WT was significantly inhibited by the miR-374a-5p mimic sequence (P<0.05), confirming the presence of a targeted regulatory relationship between ACTR2 and miR-374a-5p. These findings offer novel insights for future research directions in the diagnosis and treatment of OS.

Role of gasdermin D in inflammatory diseases: from mechanism to therapeutics.

Inflammatory diseases compromise a clinically common and diverse group of conditions, causing detrimental effects on body functions. Gasdermins (GSDM) are pore-forming proteins, playing pivotal roles in modulating inflammation. Belonging to the GSDM family, gasdermin D (GSDMD) actively mediates the pathogenesis of inflammatory diseases by mechanistically regulating different forms of cell death, particularly pyroptosis, and cytokine release, in an inflammasome-dependent manner. Aberrant activation of GSDMD in different types of cells, such as immune cells, cardiovascular cells, pancreatic cells and hepatocytes, critically contributes to the persistent inflammation in different tissues and organs. The contributory role of GSDMD has been implicated in diabetes mellitus, liver diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory bowel disease (IBD). Clinically, alterations in GSDMD levels are potentially indicative to the occurrence and severity of diseases. GSDMD inhibition might represent an attractive therapeutic direction to counteract the progression of inflammatory diseases, whereas a number of GSDMD inhibitors have been shown to restrain GSDMD-mediated pyroptosis through different mechanisms. This review discusses the current understanding and future perspectives on the role of GSDMD in the development of inflammatory diseases, as well as the clinical insights of GSDMD alterations, and therapeutic potential of GSDMD inhibitors against inflammatory diseases. Further investigation on the comprehensive role of GSDM shall deepen our understanding towards inflammation, opening up more diagnostic and therapeutic opportunities against inflammatory diseases.

Reconstruction of Allen's type IV fingertip amputation via bilateral unequal-sized hallux osteo-onychocutaneous free flaps: A retrospective study with 5-year follow-up.

PURPOSE: The reconstruction of Allen's type IV fingertip amputation is a clinical challenge. Our team designed bilateral unequal-sized hallux osteo-onychocutaneous free flaps for the long-term reconstruction of Allen's type IV fingertip amputation and conducted a retrospective study with a 5-year follow-up aims to evaluate the effects of this technique. METHODS: A retrospective analysis with a 5-year follow-up including 13 patients with Allen's type IV fingertip amputation who were admitted to our hospital from January 2010 to January 2017 was conducted. The patients were treated with bilateral unequal-sized hallux osteo-onychocutaneous free flaps. The operation time, intraoperative blood loss, and complications were recorded, and the survival rate of the transplanted flaps was calculated. During the 5-year follow-up after operation, the nail growth time was recorded and the finger appearance was observed. At the last follow-up appointment, the length, width, and girth of the reconstructed fingertip and contralateral normal fingertip, range of motion of the reconstructed fingertip and contralateral normal fingertip, Semmes-Weinstein test (for the evaluation of tactile sensation), and two-point discrimination testing results were recorded. SPSS 22.0 software was used for the statistical analysis and the data are presented as mean ± SD. RESULTS: The mean operation time was (5.62 ± 0.51) h, the mean intraoperative blood loss was (34.15 ± 3.13) mL, and the survival rate of the transplanted flaps was 100%. During the 5-year follow-up, the average nail growth time was (10.14 ± 1.98) months and the average bone union time was (3.78 ± 0.91) months. The length, width, and girth of the reconstructed fingertip were (31.52 ± 3.73) mm, (17.82 ± 1.74) mm, and (59.75 ± 3.04) mm, respectively, which did not differ from those of the contralateral normal fingertip. The range of motion of the reconstructed fingertip was (12.15 ± 2.79) degrees which is different from that of the contralateral normal fingertip. The average tactile sensation evaluated via the Semmes-Weinstein test and the average two-point discrimination test of the reconstructed fingertip were (0.39 ± 0.17) g and (7.46 ± 1.14) mm, respectively, which were not different from those of the contralateral normal fingertip. The average Maryland score of feet in the donor area was 87.66 ± 7.39, which was satisfactory. CONCLUSION: Bilateral unequal-sized hallux osteo-onychocutaneous free flaps are an effective method to reconstruct Allen's type IV fingertip amputations with a satisfactory appearance and good sensory function.

Dissociated urethral plate Onlay and standard Onlay urethroplasty for mid-distal hypospadias: A comparative study.

BACKGROUND: Urethral plate (UP) reserved Onlay urethroplasty is currently used widely in mid-distal hypospadias. However, for children with 15-30° residual curvature after degloving, only dorsal tunica albuginea plication is performed to correct penile ventral curvature (VC), and long-term follow-up showed a high recurrence rate of penile curvature. We developed a modified Onlay urethroplasty, which dissociates the UP and completely removes the tissue beneath the UP to fully correct penile curvature. Furthermore, we compared it with the standard Onlay urethroplasty to explore its rationality and feasibility. METHODS: We prospectively collected clinical data from 68 children with hypospadias who underwent standard or modified Onlay urethroplasty between September 2019 and June 2021, and evaluated the interim outcomes to identify the complications between the two groups. Additionally, we conducted histological examination of the tissue beneath the UP. RESULTS: A total of 32 patients underwent modified Onlay urethroplasty. Intraoperative curvature measurements showed that 37.5% (12/32) of the patients had completely straightened their penis after UP dissection and removal of the fibrous tissue beneath it. A total of 36 patients underwent standard Onlay urethroplasty. Totally, five fistulas each were reported in the first and second groups, and the complication rates were 15.6% and 13.9%, respectively (P > 0.05). The histological results showed that the tissue below the UP contains a large amount of collagen, mainly type I collagen. CONCLUSION: The dissociated UP Onlay urethroplasty can maximally remove factors limiting penis growth and completely correct penile curvature, without increasing the incidence of postoperative complications. Therefore, we recommend the application of the improved Onlay urethroplasty in children with mid-distal hypospadias.

Clinical and pathogen features of COVID-19-associated infections during an Omicron strain outbreak in Guangzhou, China.

Although the Omicron variant has been associated with greater transmissibility and tropism of the upper respiratory tract, the clinical and pathogenic features of patients infected with the Omicron variant during an outbreak in China have been unclear. Adults with COVID-19 were retrospectively enrolled from seven medical centers in Guangzhou, China, and clinical information and specimens ( BALF, sputum, and throat swabs) from participants were collected. Conventional detection methods, metagenomics next-generation sequencing (mNGS), and other methods were used to detect pathogens in lower respiratory tract samples. From December 2022 to January 2023, we enrolled 836 patients with COVID-19, among which 56.7% patients had severe/critical illness. About 91.4% of patients were infected with the Omicron strain (BA.5.2). The detection rate of possible co-infection pathogens was 53.4% by mNGS, including Klebsiella pneumoniae (16.3%), Aspergillus fumigatus (12.2%), and Pseudomonas aeruginosa (11.8%). The co-infection rate was 19.5%, with common pathogens being Streptococcus pneumoniae (11.5%), Haemophilus influenzae (9.2%), and Adenovirus (6.9%). The superinfection rate was 75.4%, with common pathogens such as Klebsiella pneumoniae (26.1%) and Pseudomonas aeruginosa (19.4%). Klebsiella pneumoniae (27.1%% vs 6.1%, P < 0.001), Aspergillus fumigatus (19.6% vs 5.3%, P = 0.001), Acinetobacter baumannii (18.7% vs 4.4%, P = 0.001), Pseudomonas aeruginosa (16.8% vs 7.0%, P = 0.024), Staphylococcus aureus (14.0% vs 5.3%, P = 0.027), and Streptococcus pneumoniae (0.9% vs 10.5%, P = 0.002) were more common in severe cases. Co-infection and superinfection of bacteria and fungi are common in patients with severe pneumonia associated with Omicron variant infection. Sequencing methods may aid in the diagnosis and differential diagnosis of pathogens. IMPORTANCE: Our study has analyzed the clinical characteristics and pathogen spectrum of the lower respiratory tract associated with co-infection or superinfection in Guangzhou during the outbreak of the Omicron strain, particularly after the relaxation of the epidemic prevention and control strategy in China. This study will likely prompt further research into the specific issue, which will benefit clinical practice.

Capture of RNA-binding proteins across mouse tissues using HARD-AP.

RNA-binding proteins (RBPs) modulate all aspects of RNA metabolism, but a comprehensive picture of RBP expression across tissues is lacking. Here, we describe our development of the method we call HARD-AP that robustly retrieves RBPs and tightly associated RNA regulatory complexes from cultured cells and fresh tissues. We successfully use HARD-AP to establish a comprehensive atlas of RBPs across mouse primary organs. We then systematically map RNA-binding sites of these RBPs using machine learning-based modeling. Notably, the modeling reveals that the LIM domain as an RNA-binding domain in many RBPs. We validate the LIM-domain-only protein Csrp1 as a tissue-dependent RNA binding protein. Taken together, HARD-AP is a powerful approach that can be used to identify RBPomes from any type of sample, allowing comprehensive and physiologically relevant networks of RNA-protein interactions.

Self-locking and stiffening deployable tubular structures.

Deployable tubular structures, designed for functional expansion, serve a wide range of applications, from flexible pipes to stiff structural elements. These structures, which transform from compact states, are crucial for creating adaptive solutions across engineering and scientific fields. A significant barrier to advancing their performance is balancing expandability with stiffness. Using compliant materials, these structures achieve more flexible transformations than those possible with rigid mechanisms. However, they typically exhibit reduced stiffness when subjected to external pressures (e.g., tube wall loading). Here, we utilize origami-inspired techniques and internal stiffeners to meet conflicting performance requirements. A self-locking mechanism is proposed, which combines the folding behavior observed in curved-crease origami and elastic shell buckling. This mechanism employs simple shell components, including internal diaphragms that undergo pseudofolding in a confined boundary condition to enable a snap-through transition. We reveal that the deployed tube is self-locked through geometrical interference, creating a braced tubular arrangement. This arrangement gives a direction-dependent structural performance, ranging from elastic response to crushing, thereby offering the potential for programmable structures. We demonstrate that our approach can advance existing deployment mechanisms (e.g., coiled and inflatable systems) and create diverse structural designs (e.g., metamaterials, adaptive structures, cantilevers, and lightweight panels).Weanticipate our design to be a starting point to drive technological advancement in real-world deployable tubular structures.

MCC950 promotes diabetic wound healing through modulating macrophage polarization in an MDSC-dependent manner.

Diabetic foot ulcers (DFUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Currently, there is a lack of effective therapeutic strategies. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has been reported to show strong anti-inflammation effects in many diseases. In this study, we unveiled the role of MCC950 in DFU mice model and its underlying molecular mechanisms. MCC950 could significantly accelerate diabetic wound healing, as shown by shortened healing time and better healing quality. Moreover, increased M2 phenotype macrophages and decreased pro-inflammatory genes were observed in MCC950-treated DFU mice. Additionally, myeloid-derived suppressor cells (MDSCs) were significantly increased in blood, spleen and wound tissues at different time courses. Specifically, MCC950 could recruit more MDSCs in an early phase in DFU mice, exerting an anti-inflammation effect. We identified the cell crosstalk between macrophages and MDSCs with MCC950 treatment process. Depleting MDSCs in vivo could eliminate the therapeutic effect of MCC950 on diabetic wound healing through inhibiting M2 macrophage polarization. Besides, MDSCs isolated from the wounds of MCC950 or saline treated mice were cocultured with bone marrow derived macrophage (BMDM) in a transwell system. Results confirmed that MDSCs sorted from MCC950 treated mice caused a significant increased percentage of M2 macrophages. Collectively, our findings suggest that the administration of MCC950 has the potential to accelerate diabetic wound healing by promoting M2 macrophage polarization in an MDSC-dependent manner. This study provides valuable insights into the utilization of pharmacological agents for DFU treatment.

Neutralization and Stability of JN.1-derived LB.1, KP.2.3, KP.3 and KP.3.1.1 Subvariants.

During the summer of 2024, COVID-19 cases surged globally, driven by variants derived from JN.1 subvariants of SARS-CoV-2 that feature new mutations, particularly in the N-terminal domain (NTD) of the spike protein. In this study, we report on the neutralizing antibody (nAb) escape, infectivity, fusion, and stability of these subvariants-LB.1, KP.2.3, KP.3, and KP.3.1.1. Our findings demonstrate that all of these subvariants are highly evasive of nAbs elicited by the bivalent mRNA vaccine, the XBB.1.5 monovalent mumps virus-based vaccine, or from infections during the BA.2.86/JN.1 wave. This reduction in nAb titers is primarily driven by a single serine deletion (DelS31) in the NTD of the spike, leading to a distinct antigenic profile compared to the parental JN.1 and other variants. We also found that the DelS31 mutation decreases pseudovirus infectivity in CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, the spike protein of DelS31 variants appears more conformationally stable, as indicated by reduced S1 shedding both with and without stimulation by soluble ACE2, and increased resistance to elevated temperatures. Molecular modeling suggests that the DelS31 mutation induces a conformational change that stabilizes the NTD and strengthens the NTD-Receptor-Binding Domain (RBD) interaction, thus favoring the down conformation of RBD and reducing accessibility to both the ACE2 receptor and certain nAbs. Additionally, the DelS31 mutation introduces an N-linked glycan modification at N30, which shields the underlying NTD region from antibody recognition. Our data highlight the critical role of NTD mutations in the spike protein for nAb evasion, stability, and viral infectivity, and suggest consideration of updating COVID-19 vaccines with antigens containing DelS31.

Performance of Large Language Models in Patient Complaint Resolution: Web-Based Cross-Sectional Survey.

BACKGROUND: Patient complaints are a perennial challenge faced by health care institutions globally, requiring extensive time and effort from health care workers. Despite these efforts, patient dissatisfaction remains high. Recent studies on the use of large language models (LLMs) such as the GPT models developed by OpenAI in the health care sector have shown great promise, with the ability to provide more detailed and empathetic responses as compared to physicians. LLMs could potentially be used in responding to patient complaints to improve patient satisfaction and complaint response time. OBJECTIVE: This study aims to evaluate the performance of LLMs in addressing patient complaints received by a tertiary health care institution, with the goal of enhancing patient satisfaction. METHODS: Anonymized patient complaint emails and associated responses from the patient relations department were obtained. ChatGPT-4.0 (OpenAI, Inc) was provided with the same complaint email and tasked to generate a response. The complaints and the respective responses were uploaded onto a web-based questionnaire. Respondents were asked to rate both responses on a 10-point Likert scale for 4 items: appropriateness, completeness, empathy, and satisfaction. Participants were also asked to choose a preferred response at the end of each scenario. RESULTS: There was a total of 188 respondents, of which 115 (61.2%) were health care workers. A majority of the respondents, including both health care and non-health care workers, preferred replies from ChatGPT (n=164, 87.2% to n=183, 97.3%). GPT-4.0 responses were rated higher in all 4 assessed items with all median scores of 8 (IQR 7-9) compared to human responses (appropriateness 5, IQR 3-7; empathy 4, IQR 3-6; quality 5, IQR 3-6; satisfaction 5, IQR 3-6; P<.001) and had higher average word counts as compared to human responses (238 vs 76 words). Regression analyses showed that a higher word count was a statistically significant predictor of higher score in all 4 items, with every 1-word increment resulting in an increase in scores of between 0.015 and 0.019 (all P<.001). However, on subgroup analysis by authorship, this only held true for responses written by patient relations department staff and not those generated by ChatGPT which received consistently high scores irrespective of response length. CONCLUSIONS: This study provides significant evidence supporting the effectiveness of LLMs in resolution of patient complaints. ChatGPT demonstrated superiority in terms of response appropriateness, empathy, quality, and overall satisfaction when compared against actual human responses to patient complaints. Future research can be done to measure the degree of improvement that artificial intelligence generated responses can bring in terms of time savings, cost-effectiveness, patient satisfaction, and stress reduction for the health care system.