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Cell-derived extracellular vesicles (EVs), which carry diverse biomolecules such as nucleic acids, proteins, metabolites, and lipids reflecting their cell of origin, are released under both physiological and pathological conditions. EVs have been demonstrated to mediate cell-to-cell communication and serve as biomarkers. EV-associated DNA (EV-DNA) comprises genomic and mitochondrial DNA (i.e., gDNA and mtDNA) fragments. Some studies have revealed that EV-DNA can represent the full nuclear genome and mitochondrial genome of parental cells. Furthermore, DNA fragments loaded into EVs are stable and can be transferred to recipient cells to regulate their biological functions. In this review, we summarized and discussed EV-DNA research advances with an emphasis on EV-DNA detection at the population-EV and single-EV levels, gene transfer-associated biological functions, and clinical applications as biomarkers for disease liquid biopsy. We hope that this review will provide potential directions or guidance for future EV-DNA investigations. [ABSTRACT FROM AUTHOR]

The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a common autoimmune disease characterized primarily by persistent synovial inflammation and joint destruction. In recent years, ferroptosis, as a novel form of cell death, has garnered widespread attention due to its critical role in various diseases. This review explores the potential mechanisms of ferroptosis in RA and its relationship with the pathogenesis of RA, systematically analyzing the regulatory role of ferroptosis in synovial cells, chondrocytes, and immune cells. We emphasize the evaluation of ferroptosis-related pathways and their potential as therapeutic targets, including the development and application of inhibitors and activators. Although ferroptosis shows some promise in RA treatment, its dual role and safety issues in clinical application still require in-depth study. Future research should focus on elucidating the specific mechanisms of ferroptosis in RA pathology and developing more effective and safer therapeutic strategies to provide new treatment options for RA patients. [ABSTRACT FROM AUTHOR]

Checklists are a type of cognitive aid used to guide task performance; they have been adopted as an important safety intervention throughout many high-risk industries. They have become an ubiquitous tool in many medical settings due to being easily accessible and perceived as easy to design and implement. However, there is a lack of understanding for when to use checklists and how to design them, leading to substandard use and suboptimal effectiveness of this intervention in medical settings. The design of a checklist must consider many factors including what types of errors it is intended to address, the experience and technical competencies of the targeted users, and the specific tools or equipment that will be used. Although several taxonomies have been proposed for classifying checklist types, there is, however, little guidance on selecting the most appropriate checklist type, nor how differences in user expertise can influence the design of the checklist. Therefore, we developed an algorithm to provide guidance on checklist use and design. The algorithm, intended to support conception and content/design decisions, was created based on the synthesis of the literature on checklists and our experience developing and observing the use of checklists in clinical environments. We then refined the algorithm iteratively based on subject matter experts' feedback provided at each iteration. The final algorithm included two parts: the first part provided guidance on the system safety issues for which a checklist is best suited, and the second part provided guidance on which type of checklist should be developed with considerations of the end users' expertise. [ABSTRACT FROM AUTHOR]

Patients with neurological illnesses have many palliative care needs that need to be addressed in the outpatient clinical setting. This review discusses existing models of care delivery, including services delivered by neurology teams, palliative care specialists, telehealth, and home-based programs. We review the existing literature that supports these services and ongoing limitations that continue to create barriers to necessary clinical care for this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical efficacy of 3D-printed fusion cage implantation in treating cervical spondylotic myelopathy. Methods: A retrospective analysis was performed on 52 patients with single-segment cervical spondylotic myelopathy who received anterior cervical discectomy and fusion in Affiliated Hospital of Beihua University from July 2019 to July 2022. They were divided into the 3D group and the control group. Afterward, the perioperative indicators were compared between the two groups. Meanwhile, the Japanese Orthopaedic Association (JOA) scores, Visual analogue scale (VAS) and neck disability index (NDI) were recorded pre-operation and one-year post-operation. Evaluate the fusion rate of two group of intervertebral fusion cages. Results: The JOA score and NDI of the two groups of patients were significantly improved compared to pre-operation (P<0.05), and the JOA score, JOA score improvement rate, and NDI of the 3D group were better than the control group (P<0.05), the VAS scores were significantly improved compared to pre-operation(P<0.05), but there was no statistically significant difference between the groups (P>0.05). The intervertebral height, angle, and cervical Cobb angle of the two groups of patients were significantly improved compared to pre-operation (P<0.05), and the improvement of intervertebral height, angle, and cervical Cobb angle in the 3D group was better than the control group (P<0.05). Conclusion: The clinical efficacy of 3D printed intervertebral fusion cage placement in the treatment of cervical spondylotic myelopathy may be reliable, and it would be better than traditional intervertebral fusion cages in maintaining the height, angle, cervical Cobb angle, and fusion rate of the intervertebral space. [ABSTRACT FROM AUTHOR]

This research introduces the design, implementation, and rigorous evaluation of a novel 2-channel, multi-functional therapeutic electrical stimulator, meticulously engineered to meet the stringent demands of contemporary clinical applications. The device integrates a high-speed R-2R ladder DAC and a sophisticated pulse generator unit, capable of producing twelve essential current waveforms with fully adjustable parameters, including pulse amplitude, pulse duration, and pulse repetitive frequency. The proposed driving stage unit ensures precise voltage-to-current conversion, delivering stable and accurate output currents even under varying load conditions, which effectively simulate the diverse impedance characteristics of human tissue. Extensive testing confirmed the compliance with international medical standards, notably IEC 60601-1, IEC 60601-1-2, and IEC 60601-2-10. The experimental results underscore the device's consistent operation within prescribed safety and performance thresholds, with all deviations in pulse parameters remaining well below the permissible limits. Furthermore, the proposed electrical stimulator demonstrated exceptional stability across variable load conditions, as evidenced by minimal amplitude errors and high correlation between waveform characteristics. These findings highlight the proposed device's robustness and its potential as a versatile tool for a wide range of therapeutic applications, including pain management, muscle stimulation, and nerve rehabilitation, thus marking a significant advancement in the field of therapeutic electrical stimulation. [ABSTRACT FROM AUTHOR]

Radiation‐induced tissue injury (RITI) is the most common complication in clinical tumor radiotherapy. Due to the heterogeneity in the response of different tissues to radiation (IR), radiotherapy will cause different types and degrees of RITI, which greatly limits the clinical application of radiotherapy. Efforts are continuously ongoing to elucidate the molecular mechanism of RITI and develop corresponding prevention and treatment drugs for RITI. Single‐cell sequencing (Sc‐seq) has emerged as a powerful tool in uncovering the molecular mechanisms of RITI and for identifying potential prevention targets by enhancing our understanding of the complex intercellular relationships, facilitating the identification of novel cell phenotypes, and allowing for the assessment of cell heterogeneity and spatiotemporal developmental trajectories. Based on a comprehensive review of the molecular mechanisms of RITI, we analyzed the molecular mechanisms and regulatory networks of different types of RITI in combination with Sc‐seq and summarized the targeted intervention pathways and therapeutic drugs for RITI. Deciphering the diverse mechanisms underlying RITI can shed light on its pathogenesis and unveil new therapeutic avenues to potentially facilitate the repair or regeneration of currently irreversible RITI. Furthermore, we discuss how personalized therapeutic strategies based on Sc‐seq offer clinical promise in mitigating RITI. [ABSTRACT FROM AUTHOR]

Despite being the standard treatment for end-stage liver disease, liver transplantation has limitations like donor scarcity, high surgical costs, and immune rejection risks. Mesenchymal stem cells (MSCs) and their derivatives offer potential for liver regeneration and transplantation. MSCs, known for their multipotency, low immunogenicity, and ease of obtainability, can differentiate into hepatocyte-like cells and secrete bioactive factors that promote liver repair and reduce immune rejection. However, the clinical application of MSCs is limited by risks such as aberrant differentiation and low engraftment rates. As a safer alternative, MSC-derived secretomes and extracellular vesicles (EVs) offer promising therapeutic benefits, including enhanced graft survival, immunomodulation, and reduced ischemia–reperfusion injury. Current research highlights the efficacy of MSC-derived therapies in improving liver transplant outcomes, but further studies are necessary to standardize clinical applications. This review highlights the potential of MSCs and EVs to address key challenges in liver transplantation, paving the way for innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to design and test a platform of key performance indicators (KPIs) and indices emphasizing achievements and improvement and helping decision-making. Methods: An operations research study was designed to analyze data from the Hospital Management Information System (HMIS) from July 2017 to June 2018 at the Research Institute of Ophthalmology (RIO), Giza, Egypt. The HMIS data were submitted to reform covering parameters in service delivery and corresponding indicators and indices. Data were grouped into four themes: human resources and outpatient, inpatient, and surgical operations. A total of 14 performance indicators were deployed to four specific indices and total performance indices and applied to six teams of ophthalmologists at RIO. The decision matrices were deliberated to demonstrate achievements and provide recommendations for subsequent improvements. Results: Throughout 1 year, six teams of ophthalmologists (n = 222) at RIO provided the following services: outpatient (n = 116,043), inpatient (n = 8,081), and surgical operations (n = 9,174). Teams 2, 1, and 6 were the top teams in the total performance index. Team 4 had plunges in the outpatient index, and Team 5 faced limitations in the inpatient index. Conclusion: The study provided a model for upgrading the performance of the management information system (MIS) in health organizations. The KPIs and indices were used not only for documenting successful models of efficient service delivery but also as examples of limitations for further support and interventions. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is essential for modulating hepatic homeostasis, but the impact of FGF21 on liver graft injury remains uncertain. Here, we show that high FGF21 levels in liver graft and serum are associated with improved graft function and survival in liver transplantation (LT) recipients. FGF21 deficiency aggravates early graft injury and activates arachidonic acid metabolism and regional inflammation in male mouse models of hepatic ischemia/reperfusion (I/R) injury and orthotopic LT. Mechanistically, FGF21 deficiency results in abnormal activation of the arachidonate 15-lipoxygenase (ALOX15)/15-hydroxy eicosatetraenoic acid (15-HETE) pathway, which triggers a cascade of innate immunity-dominated pro-inflammatory responses in grafts. Notably, the modulating role of FGF21/ALOX15/15-HETE pathway is more significant in steatotic livers. In contrast, pharmacological administration of recombinant FGF21 effectively protects against hepatic I/R injury. Overall, our study reveals the regulatory mechanism of FGF21 and offers insights into its potential clinical application in early liver graft injury after LT. Marginal liver grafts are associated with a higher risk of graft failure due to their increased susceptibility to ischemia-reperfusion injury. Here, the authors show the regulatory mechanism of fibroblast growth factor 21 and offer insights into its clinical application in early liver graft injury. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the performance of a semi-automated artificial intelligence (AI) software program (CerebralDoc® system) in aneurysm detection and morphological measurement. Methods: In this study, 354 cases of computed tomographic angiography (CTA) were retrospectively collected in our hospital. Among them, 280 cases were diagnosed with aneurysms by either digital subtraction angiography (DSA) and CTA (DSA group, n = 102), or CTA-only (non-DSA group, n = 178). The presence or absence of aneurysms, as well as their location and related morphological features determined by AI were evaluated using DSA and radiologist findings. Besides, post-processing image quality from AI and radiologists were also rated and compared. Results: In the DSA group, AI achieved a sensitivity of 88.24% and an accuracy of 81.97%, whereas radiologists achieved a sensitivity of 95.10% and an accuracy of 84.43%, using DSA results as the gold standard. The AI in the non-DSA group achieved 81.46% sensitivity and 76.29% accuracy, as per the radiologists' findings. The comparison of position consistency results showed better performance under loose criteria than strict criteria. In terms of morphological characteristics, both the DSA and the non-DSA groups agreed well with the diagnostic results for neck width and maximum diameter, demonstrating excellent ICC reliability exceeding 0.80. The AI-generated images exhibited superior quality compared to the standard software for post-processing, while also demonstrating a significantly reduced processing time. Conclusions: The AI-based aneurysm detection rate demonstrates a commendable performance, while the extracted morphological parameters exhibit a remarkable consistency with those assessed by radiologists, thereby showcasing significant potential for clinical application. [ABSTRACT FROM AUTHOR]

Simulation is an established transformational and experiential learning strategy in health education, drawing on creative and innovative teaching techniques. This article discusses a large-scale unfolding case study using real-time simulation with a multiprofessional facilitation team, to explore how using several simulation techniques can provide a rich learning experience for both midwifery students and their facilitators. Many midwifery students find the application of theoretical learning to practice settings a challenge, and report lacking confidence in certain elements of clinical practice, which can become more concerning in the latter stages of their training. By using multiple approaches with a student-centred outlook, this immersive simulation event positively impacted students' clinical confidence and assurance in their assessment skills, and enabled them to feel more fully prepared for everyday midwifery practice. [ABSTRACT FROM AUTHOR]

Over the past decades, liquid biopsy, especially circulating tumor DNA (ctDNA), has received tremendous attention as a noninvasive detection approach for clinical applications, including early diagnosis of cancer and relapse, real-time therapeutic efficacy monitoring, potential target selection and investigation of drug resistance mechanisms. In recent years, the application of next-generation sequencing technology combined with AI technology has significantly improved the accuracy and sensitivity of liquid biopsy, enhancing its potential in solid tumors. However, the increasing integration of such promising tests to improve therapy decision making by oncologists still has complexities and challenges. Here, we propose a conceptual framework of ctDNA technologies and clinical utilities based on bibliometrics and highlight current challenges and future directions, especially in clinical applications such as early detection, minimal residual disease detection, targeted therapy, and immunotherapy. We also discuss the necessities of developing a dynamic field of translational cancer research and rigorous clinical studies that may support therapeutic strategy decision making in the near future. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are a type of cell capable of regulating the immune system, as well as exhibiting self-renewal and multi-lineage differentiation potential. Mesenchymal stem cells have emerged as an essential source of seed cells for therapeutic cell therapy. It is crucial to cryopreserve MSCs in liquid nitrogen prior to clinical application while preserving their functionality. Furthermore, efficient cryopreservation greatly enhances MSCs' potential in a range of biological domains. Nevertheless, there are several limits on the MSC cryopreservation methods now in use, necessitating thorough biosafety assessments before utilizing cryopreserved MSCs. Therefore, in order to improve the effectiveness of cryopreserved MSCs in clinical stem cell treatment procedures, new technological techniques must be developed immediately. The study offers an exhaustive analysis of the state-of-the-art MSC cryopreservation techniques, their effects on MSCs, and the difficulties encountered when using cryopreserved MSCs in clinical applications. [ABSTRACT FROM AUTHOR]

Pure laparoscopic donor hepatectomy (PLDH) has become a standard practice for living donor liver transplantation in expert centers. Accurate understanding of biliary structures is crucial during PLDH to minimize the risk of complications. This study aims to develop a deep learning-based segmentation model for real-time identification of biliary structures, assisting surgeons in determining the optimal transection site during PLDH. A single-institution retrospective feasibility analysis was conducted on 30 intraoperative videos of PLDH. All videos were selected for their use of the indocyanine green near-infrared fluorescence technique to identify biliary structure. From the analysis, 10 representative frames were extracted from each video specifically during the bile duct division phase, resulting in 300 frames. These frames underwent pixel-wise annotation to identify biliary structures and the transection site. A segmentation task was then performed using a DeepLabV3+ algorithm, equipped with a ResNet50 encoder, focusing on the bile duct (BD) and anterior wall (AW) for transection. The model's performance was evaluated using the dice similarity coefficient (DSC). The model predicted biliary structures with a mean DSC of 0.728 ± 0.01 for BD and 0.429 ± 0.06 for AW. Inference was performed at a speed of 15.3 frames per second, demonstrating the feasibility of real-time recognition of anatomical structures during surgery. The deep learning-based semantic segmentation model exhibited promising performance in identifying biliary structures during PLDH. Future studies should focus on validating the clinical utility and generalizability of the model and comparing its efficacy with current gold standard practices to better evaluate its potential clinical applications. [ABSTRACT FROM AUTHOR]

Recent breakthroughs in medical AI have proven the effectiveness of deep learning in fetal echocardiography. However, the limited processing power of edge devices hinders real-time clinical application. We aim to pioneer the future of intelligent echocardiography equipment by enabling real-time recognition and tracking in fetal echocardiography, ultimately assisting medical professionals in their practice. Our study presents the YOLOv5s_emn (Extremely Mini Network) Series, a collection of resource-efficient algorithms for fetal echocardiography detection. Built on the YOLOv5s architecture, these models, through backbone substitution, pruning, and inference optimization, while maintaining high accuracy, the models achieve a significant reduction in size and number of parameters, amounting to only 5%-19% of YOLOv5s. Tested on the NVIDIA Jetson Nano, the YOLOv5s_emn Series demonstrated superior inference speed, being 52.8–125.0 milliseconds per frame(ms/f) faster than YOLOv5s, showcasing their potential for efficient real-time detection in embedded systems. [ABSTRACT FROM AUTHOR]

Lower urinary tract infection (UTI) is common but only rarely complicated by pyelonephritis. However, the mechanisms preventing extension to the kidney are unclear. Here, we identified neutrophil extracellular traps (NETs) in healthy human urine that provide an antibacterial defense strategy within the urinary tract. In both in vivo murine models of UTI where uropathogenic E. coli are inoculated into the bladder and ex vivo human urine models, NETs interacted with uromodulin to form large webs that entrapped the bacteria. Peptidyl arginine deiminase 4 (PADI4) inhibition in mice blocked NETosis and resulted in progression of cystitis into pyelonephritis, suggesting that NETosis of urinary neutrophils acts to prevent bacterial ascent into the kidney. Analysis of UK Biobank data revealed that genetic variants in PADI4 that associated with increased risk of rheumatoid arthritis in multiple genome-wide association studies were consistently associated with reduced susceptibility to UTI. Last, we showed that urine dipstick testing for leukocyte esterase was negative in the presence of intact blood neutrophils but became positive when neutrophils were stimulated to NET, and this could be prevented by selective PADI4 inhibition, demonstrating that this test does not detect absolute neutrophil count, as has long been assumed, but specifically detects neutrophils that have undergone NETosis. These findings highlight the role of NETosis in preventing ascending infections in the urinary tract and improve our understanding of one of the most common clinical tests in medicine. Editor's summary: Lower urinary tract infections (UTIs) rarely ascend to the kidney, but the mechanisms underlying this protection are not fully understood. Here, Stewart and colleagues identified neutrophil extracellular traps (NETs) in the urine of healthy individuals that interacted with uromodulin to form webs and entrap bacteria. Inhibition of peptidyl arginine deiminase type 4 (PADI4) reduced NETosis and increased pyelonephritis in mice challenged with uropathogenic E. coli, and an analysis of UK Biobank data revealed that variants in PADI4 were associated with reduced incidence of UTI. The authors also showed that the leukocyte esterase urine dipstick test specifically detects the presence of NETosing neutrophils, highlighting the importance of NETs in both the prevention and diagnosis of UTI. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

Immunotherapy has profoundly changed the treatment of gastric cancer, but only a minority of patients benefit from immunotherapy. Therefore, numerous studies have been devoted to clarifying the mechanisms underlying resistance to immunotherapy or developing biomarkers for patient stratification. However, previous studies have focused mainly on the tumor microenvironment. Systemic immune perturbations have long been observed in patients with gastric cancer, and the involvement of the peripheral immune system in effective anticancer responses has attracted much attention in recent years. Therefore, understanding the distinct types of systemic immune organization in gastric cancer will aid personalized treatment designed to pair with traditional therapies to alleviate their detrimental effects on systemic immunity or to directly activate the anticancer response of systemic immunity. Herein, this review aims to comprehensively summarize systemic immunity in gastric cancer, including perturbations in systemic immunity induced by cancer and traditional therapies, and the potential clinical applications of systemic immunity in the detection, prediction, prognosis and therapy of gastric cancer. [ABSTRACT FROM AUTHOR]

Wet Age-related Macular Degeneration (wet AMD) is a common ophthalmic disease that significantly impacts patients' vision. Optical coherence tomography (OCT) examination has been widely utilized for diagnosing, treating, and monitoring wet AMD due to its cost-effectiveness, non-invasiveness, and repeatability, positioning it as the most valuable tool for diagnosis and tracking. OCT can provide clear visualization of retinal layers and precise segmentation of lesion areas, facilitating the identification and quantitative analysis of abnormalities. However, the lack of high-quality datasets for assessing wet AMD has impeded the advancement of related algorithms. To address this issue, we have curated a comprehensive wet AMD OCT Segmentation Dataset (AMD-SD), comprising 3049 B-scan images from 138 patients, each annotated with five segmentation labels: subretinal fluid, intraretinal fluid, ellipsoid zone continuity, subretinal hyperreflective material, and pigment epithelial detachment. This dataset presents a valuable opportunity to investigate the accuracy and reliability of various segmentation algorithms for wet AMD, offering essential data support for developing AI-assisted clinical applications targeting wet AMD. [ABSTRACT FROM AUTHOR]

Aim: To construct evidence-based sensitive quality indicators for patients' rapid rehabilitation care after combined pancreaticoduodenectomy (PD) and to provide a reference for clinical nursing professionals to scientifically evaluate the quality of patients' rehabilitation post-PD. Background: Since PD is associated with higher surgical risk and anastomotic complications, it leads to higher complication rates and longer postoperative recovery cycles. This reiterates the need for rapid recovery of patients after PD; however, the evaluation of sensitive nursing care indicators regarding rapid recovery post-PD has not yet been established to date. Methods: Based on the Donabedian structure-process-result theory model, we used available literature, semi-structured interviews, the Delphi method, and hierarchical analysis to establish a sensitive indicator system for patients' rapid rehabilitation after PD and evaluate the importance of such indicators. Results: There were two rounds of expert correspondence, and the effective recovery rate of the questionnaires of these rounds was 100%. The expert authority coefficients, as well as the Kendall coordination coefficients of the expert opinions, were 0.859 and 0.872 as well as 0.423 and 0.431, with statistically significant differences (p < 0.05), respectively. Consequently, we developed a sensitive quality index system for patients' rapid rehabilitation care after combined PD, including 3 first-level, 12 s-level, and 23 third-level indexes, respectively. Conclusion: The constructed sensitive quality index system developed for patients' rapid rehabilitation nursing care after combined PD is standardized, practical, and aligned with the specialty characteristics. Furthermore, this might help greatly in improving the quality and safety of patients' rapid rehabilitation nursing care after combined PD, standardizing nursing management skills, and enhancing nursing quality. [ABSTRACT FROM AUTHOR]

Background: While Tourette syndrome (TS) and attention-deficit/hyperactivity disorder (ADHD) often co-occur, the nature of the relationship between their symptoms is not well understood. Network analysis of psychopathology allow for detailed examinations of symptom interactions, providing an effective approach to explore the patterns of comorbidity between TS and ADHD symptoms. Methods: This study included 3,958 participants (male/female = 3,004/954, age mean ± SD = 8.60 ± 2.25 years). We collected data on TS symptoms using the Motor Tic, Obsessions and Compulsions, Vocal Tic Evaluation Survey (MOVES), and ADHD symptoms using the Swanson, Nolan, and Pelham Rating Scale-IV (SNAP-IV). Network analysis was employed to construct a combined network of TS and ADHD symptoms at the symptom level. We utilized the expected influence (EI) and bridge EI metrics to explore the core and bridge symptoms within the network. Results: The network structure demonstrated a moderate number of non-zero connections between TS and ADHD symptoms, constituting 23.06% of all potential connections. Core symptoms in the comorbidity network included "Often has difficulty sustaining attention in tasks or play activities," "Certain bad words or thoughts keep going through my mind," and "Words come out that I can't stop or control." Bridging symptoms identified were "Words come out that I can't stop or control," "I do certain things like jumping or clapping over and over," "I can't control all my movements," and "Often talks excessively." Conclusion: The core and bridging symptoms identified in this study serve as potential therapeutic targets for the treatment of TS and ADHD comorbidity in clinical children and adolescents. [ABSTRACT FROM AUTHOR]

Background: Thymic epithelial tumors (TETs) are uncommon malignancies uniquely associated with autoimmunity and immunodeficiency. Previous studies among patients with primary immunodeficiency diseases have shown that a low calculated globulin (CG) level, obtained by subtracting albumin from total protein level, is associated with infection risk. We investigated this association among patients with TET. Methods: A cross-sectional retrospective study was performed based on electronic medical records of patients with TET treated during 2002–2024 at a tertiary care institution. For each patient, their lowest CG level and the date of occurrence were identified. The incidence of serious infection requiring hospitalization during 6 months before and 6 months after the index date was recorded. Multivariable Poisson regression models were constructed. Results: Among 101 TET patients, 96 patients (95%) had the information available to derive at least one CG level. The median lowest CG level was 2.65 g/dL (range 1.0–4.2). There were 33 serious infection episodes. Pneumonia was the most prevalent type of infection in 52% of episodes. In a multivariable analysis, a CG level below 2.0 was independently associated with the prevalence of infection with a prevalence ratio of 6.18 (95% CI: 3.12–12.23, p < 0.001). Furthermore, thymectomy was significantly associated with infection. Conclusions: Among patients with TET, a low CG level was associated with an increased prevalence of serious infections. Our limited experiences suggest that it is feasible to derive the CG level for most patients during routine clinical care. [ABSTRACT FROM AUTHOR]

Risk adjustment is often necessary for outcome quality indicators (QIs) to provide fair and accurate feedback to healthcare professionals. However, traditional risk adjustment models are generally oversimplified and not equipped to disentangle complex factors influencing outcomes that are out of a healthcare professional's control. We present VIRGO, a novel variational Bayes model trained on routinely collected, large administrative datasets to risk-adjust outcome QIs. VIRGO uses detailed demographics, diagnosis, and procedure codes to provide individualized risk adjustment and explanations on patient factors affecting outcomes. VIRGO achieves state-of-the-art on external datasets and features capabilities of uncertainty expression, explainable features, and counterfactual analysis capabilities. VIRGO facilitates risk adjustment by explaining how patient factors led to adverse outcomes and expresses the uncertainty of each prediction, allowing healthcare professionals to not only explore patient factors with unexplained variance that are associated with worse outcomes but also reflect on the quality of their clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: To develop a combined diagnostic model integrating the subclassification of the 2022 version of the American College of Radiology (ACR) Ovarian-Adnexal Reporting and Data System (O-RADS) with carbohydrate antigen 125 (CA125) and to validate whether the combined model can offer superior diagnostic efficacy than O-RADS alone in assessing adnexal malignancy risk. Methods: A retrospective analysis was performed on 593 patients with adnexal masses (AMs), and the pathological and clinical data were included. According to the large differences in malignancy risk indices for different image features in ORADS category 4, the lesions were categorized into groups A and B. A new diagnostic criterion was developed. Lesions identified as category 1, 2, 3, or 4A with a CA125 level below 35 U/ml were classified as benign. Lesions identified as category 4A with a CA125 level more than or equal to 35 U/ml and lesions with a category of 4B and 5 were classified as malignant. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the curve (AUC) of O-RADS (v2022), CA125, and the combined model in the diagnosis of AMs were calculated and compared. Results: The sensitivity, specificity, PPV, NPV, accuracy, and AUCs of the combined model were 92.4%, 96.5%, 80.2%, 98.8%, 94.1%, and 0.945, respectively. The specificity, PPV, accuracy, and AUC of the combined model were significantly higher than those of O-RADS alone (all P < 0.01). In addition, both models had acceptable sensitivity and NPV, but there were no significant differences among them (P > 0.05). Conclusion: The combined model integrating O-RADS subclassification with CA125 could improve the specificity and PPV in diagnosing malignant AMs. It could be a valuable tool in the clinical application of risk stratification of AMs. [ABSTRACT FROM AUTHOR]

Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway—IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, presenting a persisting global health burden. Neutrophils have a double-edged role in tumor progression exhibiting both pro-tumor and anti-tumor functions. CD71, also known as transferrin receptor 1, performs a critical role in cellular iron uptake and is highly expressed on proliferating cells, and especially on activated immune cells. CD71 is known to be elevated in various types of solid cancers and is associated with poor prognosis, however, the expression of CD71 on neutrophils in PDAC and its potential clinical impact is still unknown. Therefore, we analyzed CD71 on circulating neutrophils in PDAC and clinical control patients and found a significant increased expression in PDAC patients. High expression of CD71 on neutrophils in PDAC patients was associated with reduced outcome compared to low expression. CD71 on neutrophils correlated positively with the levels of proinflammatory cytokines IL-6, IFN-γ, and growth factor ligands CD40-L, and BAFF in plasma of PDAC patients. Finally, we have demonstrated that high expression of CD71 on neutrophils was also associated with an increased expression of CD39 and CD25 on circulating T-cells. Based on our findings, we hypothesize that CD71 on neutrophils is associated with tumor progression in PDAC. Further studies are required to investigate the distinct functionality of CD71 expressing neutrophils and their potential clinical application. [ABSTRACT FROM AUTHOR]

Tirzepatide, a novel GLP-1/GIP dual receptor agonist, shows significant advantages in glycemic management and weight control. By summarizing the results of the SURMOUNT and SURPASS clinical trials, we evaluate the efficacy and safety of tirzepatide in reducing blood glucose and weight. These trials indicate that tirzepatide significantly lowers HbA1c levels (with a maximum reduction of 2.24%) and promotes weight loss (up to 11.2 kg) with good tolerability. However, there are still some challenges in its clinical application, including high treatment costs and gastrointestinal discomfort. Additionally, the safety and efficacy of tirzepatide in special populations, such as patients with renal impairment, require further investigation. Future large-scale clinical trials, such as SURPASS-CVOT and SUMMIT, are expected to further verify the long-term benefits of tirzepatide in cardiovascular health management, providing stronger evidence for its comprehensive treatment of diabetes and its complications. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the efficacy and safety of berberine(BBR) plus 5-aminosalicylic acid (5-ASA) for treating ulcerative colitis (UC). Methods: A comprehensive search was conducted in electronic databases, including Medline/PubMed, Sinomed, Embase, CNKI, Wanfang, and VIP, through January 2024 to identify all randomized controlled trials (RCTs) that administered BBR conjunction in standard therapy(5-ASA) for to support the treatment of UC. The data were synthesized using a meta-analysis approach with RevMan 5.4.1. The primary endpoint was the clinical efficacy rate. In contrast, the secondary endpoints included the Baron score, disease activity index (DAI) score, symptom relief latency, inflammatory markers, immunological indicators, and adverse events. Results: In this analysis, 10 RCTs comprising 952 patients with UC were examined. BBR considerably improved the clinical efficacy rate (RR = 1.22, 95% CI [1.15, 1.30], P < 0.00001), attenuated the Baron score (SMD = -1.72, 95% CI [-2.30, -1.13], P < 0.00001) and reduced the DAI score (SMD = -2.93, 95% CI [-4.42, -1.43], P < 0.00001). Additionally, it ameliorated clinical symptoms (SMD = -2.74, 95% CI [-3.45, 2.02], P < 0.00001), diminished inflammatory responses (SMD = -1.59, 95% CI [-2.14, 1.04], P < 0.00001), and modulated immune reactions (SMD = 1.06,95% CI [0.24,1.87], P <0.00001). Nonetheless, the impact of BBR on reducing adverse reactions was not statistically significant (RR = 0.75, 95% CI [0.42, 1.33], P > 0.05). Conclusion: BBR demonstrates substantial efficacy in treating UC without causing severe adverse reactions and may serve as a viable complementary therapy. However, its clinical application warrants confirmation by additional high-quality, low-bias RCTs. [ABSTRACT FROM AUTHOR]

Background: Adalimumab induces the production of anti-drug antibodies (ADA) that may lead to reduced drug concentration and loss-of-response, posing significant clinical challenges. However, traditional immunoassays have limitations in terms of sensitivity and drug-tolerance, hindering the insights of ADA response. Methods: Herein, we developed an integrated immunoassay platform combining the electrochemiluminescence immunoassay with immunomagnetic separation strategy. A longitudinal cohort study involving 49 patients with ankylosing spondylitis was carried out to analyze the dynamic profiles of ADA and to investigate the impact of ADA on adalimumab pharmacokinetics using a population pharmacokinetic model. Additionally, cross-sectional data from 12 patients were collected to validate the correlation between ADA levels and disease relapse. Results: The ADA assay demonstrated high sensitivity (0.4 ng/mL) and drugtolerance (100 mg/mL), while the neutralizing antibodies (NAB) assay showed a sensitivity of 100 ng/mL and drug-tolerance of 20 mg/mL. Analysis of the longitudinal cohort revealed that a majority of patients (44/49, 90%) developed persistent ADA within the first 24 weeks of treatment. ADA levels tended to plateau over time after an initial increase during the early immune response phase. Further, nearly all of the tested patients (26/27, 96%) were classified as NAB positive, with a strong correlation between ADA levels and neutralization capacity (R2 = 0.83, P < 0.001). Population pharmacokinetic modeling revealed a significant positive association between model-estimated individual clearance and observed ADA levels. Higher ADA levels were associated with adalimumab clearance and disease relapse in a cross-sectional cohort, suggesting a promising ADA threshold of 10 for potential clinical application. Moreover, the IgG class was the primary contributor to ADA against adalimumab and the apparent affinity exhibited an increasing trend over time, indicating a T-cell dependent mechanism for ADA elicitation by adalimumab. Conclusion: In summary, this integrated immunoassay platform shows promise for in-depth analysis of ADA against biologics, offering fresh insights into immunogenicity and its clinical implications. [ABSTRACT FROM AUTHOR]

Background: Acral melanoma presents distinct biological characteristics compared to cutaneous melanoma. While adjuvant therapeutic strategies for high-risk resected acral melanoma closely resemble those for cutaneous melanoma, the evidence supporting the clinical application of adjuvant therapy for acral melanoma remains inadequate. Our aim was to systematically analyze the efficacy and safety profile of adjuvant therapy in acral melanoma. Methods: This systematic review adhered to a pre-registered protocol. We comprehensively searched four electronic databases and reference lists of included articles to identify eligible studies. The primary outcome was therapeutic efficacy, and the secondary outcome was adverse events (AEs). Results: This systematic review included 11 studies with 758 acral melanoma patients undergoing adjuvant therapy. High-dose interferon α-2b (IFN) regimens showed no significant difference in recurrence-free survival (RFS), though the longer regimen was linked to increased hepatotoxicity. Adjuvant anti-PD-1 therapy demonstrated varying efficacy, with improved RFS in patients who experienced immune-related AEs. Targeted therapy with dabrafenib plus trametinib achieved high 12-month RFS in patients with BRAF-mutated acral melanoma. Comparative studies suggested that adjuvant anti-PD-1 therapy is similarly effective to IFN in prolonging survival for high-risk acral melanoma patients. Additionally, prior treatment with pegylated IFN enhanced RFS in patients receiving adjuvant pembrolizumab. Conclusion: High-dose IFN was widely used as adjuvant therapy for acral melanoma, but serious AEs prompted the search for alternatives. Adjuvant anti-PD-1 therapy shows promise, though it may be less effective than in non-acral melanoma. Further prospective studies are needed to determine the optimal adjuvant treatment for acral melanoma. [ABSTRACT FROM AUTHOR]

Lipedema is a chronic disorder primarily affecting women, characterized by abnormal fat deposition in the extremities, leading to pain, mobility issues, and psychological distress. These fat deposits are clear-cut and spare hands and feet. Often misdiagnosed as lymphedema, its prevalence remains uncertain due to a lack of universally accepted diagnostic criteria and difficulty in differentiating it from obesity or lymphedema. Genetic factors and hormonal influences are likely related to the pathophysiology of the disease, though the specific causes remain unknown. Imaging techniques may aid evaluation, but no definitive test exists, and diagnosis is made clinically. Conservative treatments such as lifestyle modifications and compression garments are considered first-line treatments, while surgical options such as liposuction and lipectomy are reserved for severe or refractory cases. Psychological support may be recommended, given lipedema's impact on quality of life and self-esteem. This review aims to present the current understanding of this condition, including challenges in diagnosis, current guideline recommendations for clinical care, and associated comorbid conditions. [ABSTRACT FROM AUTHOR]

Significance: Although the depth detection limit of fluorescence objects in tissue has been studied, reports with a model including noise statistics for designing the optimum measurement configuration are missing. We demonstrate a variance analysis of the depth detection limit toward clinical applications such as noninvasively assessing the risk of aspiration. Aim: It is essential to analyze how the depth detection limit of the fluorescence object in a strong scattering medium depends on the measurement configuration to optimize the configuration. We aim to evaluate the depth detection limit from theoretical analysis and phantom experiments and discuss the source-detector distance that maximizes this limit. Approach: Experiments for detecting a fluorescent object in a biological tissuemimicking phantom of ground beef with background emission were conducted using continuous wave fluorescence measurements with a point source-detector scheme. The results were analyzed using a model based on the photon diffusion equations. Then, variance analysis of the signal fluctuation was introduced. Results: The model explained the measured fluorescence intensities and their fluctuations well. The variance analysis showed that the depth detection limit in the presence of ambient light increased with the decrease in the source-detector distance, and the optimum distance was in the range of 10 to 15 mm. The depth detection limit was found to be ~30 mm with this optimum distance for the phantom. Conclusions: The presented analysis provides a guide for the optimum design of the measurement configuration for detecting fluorescence objects in clinical applications. [ABSTRACT FROM AUTHOR]

Cardiac magnetic resonance imaging (MRI) is widely used for non-invasive assessment of cardiac morphology, function, and tissue characteristics due to its exquisite soft-tissue contrast. However, it remains time-consuming and requires proficiency, making it costly and limiting its widespread use. Traditional cardiac MRI is inefficient as signal acquisition is often limited to specific cardiac phases and requires complex view planning, parameter adjustments, and management of both respiratory and cardiac motion. Recent efforts have aimed to make cardiac MRI more efficient and accessible. Among these innovations, the free-running framework enables 5D whole-heart imaging without the need for an electrocardiogram signal, respiratory breath-holding, or complex planning. It uses a fully self-gated approach to extract cardiac and respiratory signals directly from the acquired image data, allowing for more efficient coverage in time and space without the need for electrocardiogram gating, triggering, navigators, or breath-holds. This review provides a comprehensive overview of the free-running framework, detailing its history, concepts, recent improvements, and clinical applications. [ABSTRACT FROM AUTHOR]

Background: The HHUS market is very complex due to a multitude of equipment variants and several different device manufacturers. Only a few studies have compared different HHUS devices under clinical conditions. We conducted a comprehensive prospective observer study with a direct comparison of nine different HHUS devices in terms of B-scan quality, device handling, and software features under abdominal imaging conditions. Methods: Nine different HHUS devices (Butterfly iQ+, Clarius C3HD3, D5CL Microvue, Philips Lumify, SonoEye Chison, SonoSite iViz, Mindray TE Air, GE Vscan Air, and Youkey Q7) were used in a prospective setting by a total of 12 experienced examiners on the same subjects in each case and then assessed using a detailed questionnaire regarding B-scan quality, handling, and usability of the software. The evaluation was carried out using a point scale (5 points: very good; 1 point: insufficient). Results: In the overall evaluation, Vscan Air and SonoEye Chison achieved the best ratings. They achieved nominal ratings between "good" (4 points) and "very good" (5 points). Both devices differed significantly (p < 0.01) from the other seven devices tested. Among the HHUS devices, Clarius C3HD3 and Vscan Air achieved the best results for B-mode quality, D5CL Microvue achieved the best results for device handling, and SonoEye Chison and Vscan Air achieved the best results for software. Conclusions: This is the first comprehensive study to directly compare different HHUS devices in a head-to-head manner. While the majority of the tested devices demonstrated satisfactory performance, notable discrepancies were observed between them. In particular, the B-scan quality exhibited considerable variation, which may have implications for the clinical application of HHUS. The findings of this study can assist in the selection of an appropriate HHUS device for specific applications, considering the clinical objectives and acknowledging the inherent limitations. [ABSTRACT FROM AUTHOR]

Background/Objectives: We aimed to investigate the influence of cardiorespiratory fitness (CRF) and body composition on arterial stiffness. Methods: Carotid-to-femoral pulse wave velocity (cfPWV) and aortic systolic (ASBP) and diastolic (ADBP) blood pressure were compared between upper and lower tertiles of oxygen consumption at the aerobic threshold (VO2AerT), peak oxygen consumption (VO2peak), percentage of fat mass (FM%), and body mass index (BMI) in sixty adolescents (30 males and 30 females, 14.9 ± 2.1 years old). A stepwise multivariable linear regression analysis was performed to investigate the independent associations between VO2AerT and VO2peak and cfPWV, and between BMI and FM% and cfPWV with adjustments for age, sex, ASBP, and ADBP. Results: cfPWV and ADBP were lower in the second and third VO2AerT tertiles compared to the first tertile (cfPWV, 4.7 ± 0.5 and 4.7 ± 0.5 vs. 5.3 ± 0.8 m/s, p < 0.01; ADBP, 62 ± 7 and 62 ± 7 vs. 70 ± 8 mmHg, p < 0.01). ASBP was lower in the third VO2AerT tertile compared to the first tertile (94 ± 7 vs. 101 ± 12 mmHg, p = 0.05). ADBP was lower in the second VO2peak tertile compared to the first tertile (62 ± 7 vs. 68 ± 9 mmHg, p = 0.03). ASBP was lower in the first and second BMI tertiles compared to the third tertile (95 ± 8 and 95 ± 7 vs. 102 ± 11 mmHg, p = 0.02). The eight-variable model significantly contributed to the variance of cfPWV (F(8, 51) = 7.450, p < 0.01), accounting for 47% of the variance. Individually, age (p < 0.05) and ADBP (p < 0.01) significantly predicted cfPWV. Conclusions: Submaximal indicators of CRF such as VO2AerT should be considered as a part of the risk stratification of cardiovascular disease in healthy adolescents. [ABSTRACT FROM AUTHOR]

Introduction: Assessment of drug-related adverse events is essential to fully understand the benefit–risk balance of any drug exposure, weighing efficacy versus safety. This is needed for both drug labeling and clinical decision-making. Assessment is based on seriousness, severity and causality, be it more difficult to apply in neonates. Adverse event detection or prevention in the neonatal clinical setting is also more complicated because of polypharmacy, and off-label or unlicensed pharmacotherapy. Areas covered: Tools became available to assess severity and causality of adverse events in neonates recruited in clinical trials. The first version of the Neonatal Adverse Event severity score (NAESS) reduced the inter-observer variability. Causality tools like the Naranjo score were also tailored to neonates. These tools are also instrumental to support proactive pharmacovigilance in clinical care, while multidisciplinary care teams and computerized pharmacovigilance using advanced data analysis, like machine learning are emerging approaches to develop effective decision strategies. Expert opinion: All stakeholders involved in development of medicines or its clinical use should be aware of the limitations of the currently available assessment tools. Extension and optimization of these tools, advanced data analysis approaches, and capturing the variability in time-dependent physiology are warranted to improve pharmacovigilance in neonates. [ABSTRACT FROM AUTHOR]

Background/Objectives: Surgical navigation has advanced maxillofacial surgery since the 1990s, bringing benefits for various indications. Traditional registration methods use fiducial markers that are either invasively bone-anchored or attached to a dental vacuum splint and offer high accuracy but necessitate additional imaging with increased radiation exposure. We propose a novel, non-invasive registration protocol using a CAD/CAM dental splint based on high-resolution intraoral scans. Methods: The effectiveness of this method was experimentally evaluated with an ex vivo 3D-printed skull measuring the target registration error (TRE). Surgical application is demonstrated in two clinical cases. Results: In the ex vivo model, the new CAD/CAM-splint-based method achieved a mean TRE across the whole facial skull of 0.97 ± 0.29 mm, which was comparable to traditional techniques like using bone-anchored screws (1.02 ± 0.23 mm) and dental vacuum splints (1.01 ± 0.33 mm), while dental anatomical landmarks showed a lower accuracy with a mean TRE of 1.84 ± 0.44 mm. Multifactorial ANOVA confirmed significant differences in TRE based on the registration method and the navigated level of the facial skull (p < 0.001). In clinical applications, the presented method demonstrated high accuracy for both midfacial and mandibular surgeries. Conclusions: Our results suggest that this non-invasive CAD/CAM-splint-based method is a viable alternative to traditional fiducial marker techniques, with the potential for broad application in maxillofacial surgery. This approach retains high accuracy while eliminating the need for supplementary imaging and reduces patient radiation exposure. Further clinical trials are necessary to confirm these findings and optimize splint design for enhanced navigational accuracy. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter the bloodstream and acquire a great potential for their use for personalized cancer management. In this review, we describe the current understanding of and advances in the clinical employment of CTCs. Although considered rare and fleeting, CTCs are now recognized as key players favoring the development of cancer metastasis and disease recurrence, particularly in malignant melanoma, lung, breast, and colorectal cancer patients. To date, the advancements in technology and the development of several successful approaches, also including immunomagnetic enrichment allow for a reliable and reproducible detection and characterization of CTCs. Those innovative methodologies improved the isolation, quantification, and characterization of CTCs from the blood of cancer patients, providing extremely useful evidence and new insights into the nature of the tumor, its epithelial/mesenchymal profile, and its potential resistance to therapy. In fact, in addition to their prognostic and predictive value, CTCs could serve as a valuable instrument for real-time monitoring of treatment response and disease recurrence, facilitating timely interventions and thus improving patient outcomes. However, despite their potential, several challenges hinder the widespread clinical utility of CTCs: (i) CTCs' rarity and heterogeneity pose technical limitations in isolation and characterization, as well as significant hurdles in their clinical implementation; (ii) it is mandatory to standardize CTC detection methods, optimize the sample processing techniques, and integrate them with existing diagnostic modalities; and (iii) the need for the development of new techniques, such as single-cell analysis platforms, to enhance the sensitivity and specificity of CTC detection, thereby facilitating their integration into routine clinical practice. In conclusion, CTCs represent a potential extraordinary tool in cancer diagnostics and therapeutics, offering unprecedented opportunities for personalized medicine and precision oncology. Moreover, their ability to provide real-time insights into tumor biology, treatment response, and disease progression underlines a great potential for their clinical application to improve patients' outcomes and advance our understanding of cancer biology. [ABSTRACT FROM AUTHOR]

Genome sequencing has revealed frequent mutations in Ras homolog family member A (RHOA) among various cancers with unique aberrant profiles and pathogenic effects, especially in peripheral T-cell lymphoma (PTCL). The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type, thereby leading to different functional and biological properties, which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors. However, the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated. Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways. The promising potential of targeting RHOA as a therapeutic modality is also outlined. This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients. [ABSTRACT FROM AUTHOR]

Background: Activating the cytosolic innate immune sensor, the cGAS-STING pathway, holds great promise for enhancing antitumor immunity, particularly in combination with immune checkpoint inhibitors (ICIs). However, the clinical application of STING agonists is often hindered by poor tumor accumulation, limited cellular uptake, and rapid clearance. To address these challenges, we developed a human serum albumin (HSA)-based nanoreactor system for the efficient delivery of the STING agonist SR-717, aiming to improve its antitumor efficacy. Methods: Using a biomineralization technique, we encapsulated SR-717 within HSA nanocages to form SH-NPs. These nanoparticles were characterized in terms of size, stability, and cellular uptake, and their ability to activate the STING pathway was assessed in both in vitro and in vivo models, including freshly isolated human renal tumor tissues. In vivo antitumor efficacy was evaluated in a murine renal tumor model, and immune responses were measured. Results: SH-NPs exhibited enhanced stability, efficient cellular uptake, and superior tumor accumulation compared to free SR-717. They robustly activated the STING pathway, as evidenced by increased phosphorylation of TBK1 and IRF3, along with elevated IFN-β production. Additionally, SH-NPs reshaped the immunosuppressive tumor microenvironment, promoting T-cell-mediated immunity and improving the therapeutic efficacy of checkpoint blockade in murine models. The validation in human renal tumor tissues further highlighted their potential for clinical translation. Importantly, SH-NPs were well tolerated with minimal systemic toxicity. Conclusions: This study underscores the potential of HSA-based nanoparticles for the targeted delivery of STING agonists, effectively enhancing antitumor immunity and improving cancer immunotherapy outcomes. SH-NPs offer a promising solution to the limitations of current STING agonists in clinical settings. [ABSTRACT FROM AUTHOR]

[68Ga]Ga-FAP-2286 is a new peptide-based radiopharmaceutical for positron-emission tomography (PET) that targets fibroblast activation protein (FAP). This article describes in detail the automated synthesis of [68Ga]Ga-FAP-2286 using a commercially available synthesis tool that includes quality control for routine clinical applications. The synthesis was performed using a Scintomics GRP-3V module and a GMP grade 68Ge/68Ga generator. A minor alteration for transferring the eluate to the module was established, eliminating the need for new method programming. Five batches of [68Ga]Ga-FAP-2286 were tested to validate the synthesis. A stability analysis was conducted up to 3 h after production to determine the shelf-life of the finished product. The automated synthesis on the Scintomics GRP-3V synthesis module was found to be compliant with all quality control requirements. The shelf-life of the product was set to 2 h post-production based on the stability study. A patient suffering from cholangiocellular carcinoma that could not be clearly detected by conventional imaging, including a [18F]FDG-PET/CT, highlights the potential use of [68Ga]Ga-FAP-PET/CT. [ABSTRACT FROM AUTHOR]

In-vivo flow cytometry is a noninvasive real-time diagnostic technique that facilitates continuous monitoring of cells without perturbing their natural biological environment, which renders it a valuable tool for both scientific research and clinical applications. However, the conventional approach for improving classification accuracy often involves labeling cells with fluorescence, which can lead to potential phototoxicity. This study proposes a label-free in-vivo flow cytometry technique, called dynamic YOLOv4 (D-YOLOv4), which improves classification accuracy by integrating absorption intensity fluctuation modulation (AIFM) into YOLOv4 to demodulate the temporal features of moving red blood cells (RBCs) and platelets. Using zebrafish as an experimental model, the D-YOLOv4 method achieved average precisions (APs) of 0.90 for RBCs and 0.64 for thrombocytes (similar to platelets in mammals), resulting in an overall AP of 0.77. These scores notably surpass those attained by alternative network models, thereby demonstrating that the combination of physical models with neural networks provides an innovative approach toward developing label-free in-vivo flow cytometry, which holds promise for diverse in-vivo cell classification applications. [ABSTRACT FROM AUTHOR]

Background: Clinical laboratories frequently implement the same tests and internal quality control (QC) rules on identical instruments. It is unclear whether individual QC targets for each analyser or ones that are common to all instruments are preferable. This study modelled how common QC targets influence assay error detection before examining their effect on real-world data. Methods: The effect of variable bias and imprecision on error detection and false rejection rates when using common or individual QC targets on two instruments was simulated. QC data from tests run on two identical Beckman instruments (6-month period, same QC lot, n > 100 points for each instrument) determined likely real-world consequences. Results: Compared to individual QC targets, common targets had an asymmetrical effect on systematic error detection, with one instrument assay losing detection power more than the other gained. If individual in-control assay standard deviations (SDs) differed, then common targets led to one assay failing QC more frequently. Applied to two analysers (95 QC levels and 45 tests), common targets reduced one instrument's error detection by ≥ 0.4 sigma on 15/45 (33%) of tests. Such targets also meant 14/45 (31%) of assays on one in-control instrument would fail over twice as frequently as the other (median ratio 1.62, IQR 1.20–2.39) using a 2SD rule. Conclusions: Compared to instrument-specific QC targets, common targets can reduce the probability of detecting changes in individual assay performance and cause one in-control assay to fail QC more frequently than another. Any impact on clinical care requires further investigation. [ABSTRACT FROM AUTHOR]

Introduction: The threshold concept framework (TCF) was first described nearly 20 years ago, but its application in the field of medical education has recently seen a significant growth of interest with a diverse range of literature published on the subject. The transformative nature of threshold concepts (TCs) offers potential for the design of learning experiences and curricula across the medical education continuum. A scoping review was conducted to map the extent of the current literature regarding TCs in medical education—to describe the types of available evidence and its focus—and identify research gaps. Methods: The review followed the JBI Manual for Evidence Synthesis approach for scoping reviews. Four databases and two additional websites were searched for articles exploring TCs in medical education. Data were analysed using quantitative and qualitative thematic approaches. A framework of conceptual change was used to synthesise the TCs identified. Results: Thirty‐six papers, spanning undergraduate, postgraduate and continuing medical education, were included in the final analysis. The most frequent application of the TCF was in the identification of TCs, which related to basic scientific knowledge, ways of thinking and ways of practising in medicine. Uncertainty, patient care, clinical reasoning and professional identify formation were themes that emerged at multiple stages of training. Several papers evaluated the use of the TCF in teaching. Conclusion: The understanding and embodiment of TCs increases in complexity across the medical education continuum, with TCs recurring with changes in clinical environment and responsibilities. This lends support to a holistic approach to curriculum design spanning all stages of training. Further research is needed to develop a consistent approach for describing and applying the TCF in medical education and to address how the TCF can be used in teaching and how threshold crossing can be measured. Understanding and embodiment of threshold concepts across the medical education continuum is argued through this review to support a holistic approach to curriculum design. [ABSTRACT FROM AUTHOR]

In acute care settings, interactions between providers and tools drive clinical decision-making. Most studies of decision-making focus on individual cognition and fail to capture critical collaborations. Distributed Cognition (DCog) theory provides a framework for examining the dispersal of tasks among agents and artifacts, enhancing the investigation of decision-making and error. This scoping review maps the evidence collected in empiric studies applying DCog to clinical decision-making in acute care settings and identifies gaps in the existing literature. Thirty-seven articles were included. The majority (n=30) used qualitative methods (observations, interviews, artifact analysis) to examine the work of physicians (n=28), nurses (n=27), residents (n=16), and advanced practice providers (n=12) in intensive care units (n=18), operating rooms (n=7), inpatient units (n=7) and emergency departments (n=5). Information flow (n=30) and task coordination (n=30) were the most frequently investigated elements of DCog. Provider-artifact (n=35) and provider-provider (n=30) interactions were most explored. Electronic (n=18) and paper (n=15) medical records were frequently described artifacts. Seven prominent themes were identified. DCog is an underutilized framework for examining how information is obtained, represented, and transmitted through complex clinical systems. DCog offers mechanisms for exploring how technologies, like EMRs, and workspaces can help or hinder clinical decision-making. [ABSTRACT FROM AUTHOR]

BCI devices are increasingly being used to create interactive interfaces between users and their own psychophysiological signals. Over the years, these systems have seen strong development as they can enable people with limited mobility to make certain decisions to alter their environment. Additionally, their portability and ease of use have allowed a field of research to flourish for the study of cognitive and emotional processes in natural settings. The study of creativity, especially little creativity (little-c), is one example, although the results of this cutting-edge research are often poorly systematized. The purpose of the present paper, therefore, was to conduct a scoping review to describe and systematize the various studies that have been conducted on the application potential of BCI to the field of creativity. Twenty-two papers were selected that collect information on different aspects of creativity, including clinical applications; art experience in settings with high ecological validity; BCI for creative content creation, and participants' engagement. Critical issues and potentialities of this promising area of study are also presented. Implications for future developments towards multi-brain creativity settings and C2 are discussed. [ABSTRACT FROM AUTHOR]

Evidence-based practice (EBP), in combination with clinical expertise and patient values and wishes, enables delivery of exceptional patient-centred care. Providing our perioperative patients care that is informed by best evidence has been proven to provide a safer and higher standard of care. Best evidence forms the basis for standards and guidelines for nursing practice published by organisations such as Australian College of Perioperative Nurses (ACORN), Australian and New Zealand College of Anaesthetists (ANZCA) and Australian Commission on Safety and Quality in Health Care (ACSQHC). While perioperative nurses strive to provide the best possible care for their patients there is sometimes a 'mismatch' in the clinical environment when nurses revert to the use of tradition-based practices rather than providing care that has been based on best evidence that would be safer for their patients. The reasons for this are complex and involve, in part, a lack understanding of research and evidence, and a lack of time. As higher education and a deeper understanding of and appreciation for research and evidence has been shown to enhance the uptake of evidence- based perioperative practice, good nursing leadership, encouragement and resources are needed to spearhead education in this vital area. This discussion paper will present some of the barriers and facilitators to the provision of evidence-based care in the clinical environment. However, while researching this topic revealed a significant quantity of low-level research that provided similar findings, there was a paucity of rigorous high-level research. This indicates the need for further research in this vital area. [ABSTRACT FROM AUTHOR]

The impact of a pharmacist as a dedicated member of multidisciplinary intensive care unit (ICU) and emergency department (ED) teams has repeatedly been described in the literature for over 20 years. A 2020 position paper published by the Society of Critical Care Medicine and the American College of Clinical Pharmacy recommended the optimal practice model include critical care pharmacists providing direct patient care 24 h a day, 7 days a week. The objective of this paper is to describe the expansion and evolution of clinical pharmacy services provided in the ICU and ED at a large academic health center, beginning in 2015 and accelerated in the face of a global pandemic. This was made possible through a combination of creating new positions and reallocating existing positions to substantially increase ICU and ED clinical pharmacy coverage. Over a 7 year period, the emergency medicine and critical care clinical pharmacy team expanded from six full time equivalent (FTE) employees in 2015 to 16 FTEs in early 2022. This allowed for reduced pharmacist to patient ratios, the expansion of clinical pharmacy services from primarily weekday hours to a 24 h per day coverage model, 7 days a week, and to better support clinical pharmacy specialists providing these services. Rapid expansion of around the clock clinical pharmacy services was only possible through collaboration between clinical and operations pharmacy managers and feedback from members of the multidisciplinary team. [ABSTRACT FROM AUTHOR]