Search Results (76)

Background: Lung adenocarcinoma (LUAD) develops through a stepwise pathological status from atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA) to invasive adenocarcinoma (IA). Although malignant epithelial evolution during this process has been increasingly characterized, the dynamic remodeling of cancer-associated fibroblasts (CAFs) and their contribution to the immunosuppressive tumor microenvironment (TME) remain incompletely explored. Methods: Single-cell RNA sequencing data from treatment-naïve LUAD lesions, including AAH, AIS, MIA, and IA, were analyzed together with external bulk transcriptomic cohorts. CAF subsets were characterized according to their transcriptional features, inferred developmental states, transcription factor activity, functional programs, and predicted cell–cell interactions. Ligand–receptor analysis was used to examine MIF-related communication between epithelial cells and CAFs. MIF-related genes were then used to develop a machine learning-based prognostic signature in the TCGA-LUAD cohort, followed by validation in independent GEO cohorts. Results: Single-cell transcriptomic analysis of 131,639 cells from 25 treatment-naïve LUAD lesions identified six CAF subtypes, including alveolar CAFs, antigen-presenting CAFs, extracellular matrix CAFs, EndMT-like CAFs, inflammatory CAFs, and myofibroblastic CAFs. CAF composition differed across pathological stages, with MIA lesions showing a distinct enrichment of eCAFs and reduced proportions of inflammatory and myofibroblastic CAF populations. Compared with pre-invasive lesions, IA lesions exhibited increased proportions of exhausted CD4+ and CD8+ T cells together with reduced cytotoxic features. Cell–cell communication analysis identified enhanced epithelial–CAF interactions in IA, including enrichment of MIF-CD74/CD44 signaling. Based on MIF-related genes, a machine learning prognostic signature was developed and validated in independent cohorts, consistently stratifying patients into distinct risk groups with significantly different survival outcomes. Conclusions: These findings suggest that CAF-related stromal remodeling is associated with immune suppression during LUAD progression. MIF-mediated epithelial–CAF communication may be involved in the formation of an immunosuppressive microenvironment and is associated with poor prognosis. The MIF-related signature may provide a useful approach for prognostic stratification in LUAD. Full article

The heterogeneity of tumor cells facilitates their dynamic adaptation to tumor microenvironmental pressures throughout progression. Nevertheless, the mechanisms underlying intercellular communication and transformation among heterogeneous tumor cells remain inadequately understood. In this study, we indicate that Ephrin type-A receptor 2 (EphA2) is heterogeneously expressed in gastric cancer (GC) tumor cells, with those exhibiting elevated EphA2 (EphA2^High) expression demonstrating enhanced migratory and invasive capabilities. EphA2^High cells facilitate the transfer of EphA2 via exosomes, which subsequently localize on the membrane of EphA2^Low cells, thereby activating the ERK signaling pathway in a ligand-independent manner. This process promotes the transformation of EphA2^Low cells and contributes to the progression of GC. An investigation into the correlation between serum levels and tumor metastasis in patients with GC revealed that those with lymph node metastasis exhibited higher levels of serum exosomal EphA2. This study elucidates the process of dominant group formation within heterogeneous tumor cells and suggests the viability of exosomal EphA2 as a potential biomarker for further clinical investigation. Full article

Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-β, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type–specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies. Full article

Psoriasis is a chronic immune-mediated disease driven by genetic susceptibility and environmental factors, including microbial exposure. While HLA-C-linked variants represent the strongest genetic risk factors, their relationship with the cutaneous microbiome remains incompletely understood. This study aimed to investigate host–microbiome interactions in psoriasis through integrative multi-omics analysis. Skin microbiome profiling using 16S rRNA sequencing and targeted genotyping of psoriasis-associated single-nucleotide polymorphisms (SNPs) was performed in lesional and non-lesional skin from patients with plaque psoriasis and in healthy controls. Integrated analysis was conducted using supervised multivariate modeling (DIABLO) to identify coordinated genetic and microbial features associated with disease status. Combined genetic and microbial signatures differentiated lesional, non-lesional, and healthy skin. Variants within the HLA-C susceptibility region, including rs12191877, rs10484554, and rs4406273, showed contributions to group separation and demonstrated positive associations with Peptostreptococcus anaerobius. Associations involving ERAP1 variants linked antigen-processing pathways with inflammation-associated microbial taxa in lesional skin. Importantly, genotype–microbiome correlations were also detected in clinically non-lesional skin, where an increased psoriasis risk allele dosage co-varied with a higher relative abundance of P. anaerobius and Aerococcus urinae. In contrast, commensal-associated taxa were enriched in healthy controls and formed genotype-linked clusters only in non-lesional skin. These findings suggest that psoriasis is characterized by coordinated host genetic and microbial interaction patterns centered on antigen presentation pathways. The presence of a genotype–microbiome coupling in non-lesional skin may indicate that genetically determined immune configurations could shape microbial community structure prior to visible lesion development. Rather than reflecting uniform dysbiosis, psoriasis may represent a dynamic host–microbe ecosystem in which genetic susceptibility influences microbial persistence and inflammatory readiness. Full article

Background: In 2024, Reddit, an emerging social media platform, saw a 50% increase in monthly users to nearly 100 million. Reddit has also emerged as a significant space for discussions about health conditions, including epilepsy, which affects about 50 million people globally. Purpose: This study aims to explore trends in the volume, timing, themes, emotional tone, and sentiment of posts on the r/Epilepsy subreddit from 1 December 2023 to 31 December 2024. Methods: We collected 25,222 original English-language posts from r/Epilepsy using Reddit’s Application Programming Interface (API). Data extraction was restricted to English-language submissions to ensure compatibility with sentiment and thematic analyses. We analyzed post volume and timing using chi-square tests and Poisson regression. Emotional tone was measured using TextBlob (version 0.19.0), while compound sentiment scores were calculated via VADER (Valence Aware Dictionary and Sentiment Reasoner) (NLTK version 3.9.1). A Pearson correlation assessed agreement between sentiment and emotional tone, with statistical significance set at p < 0.05. Thematic analysis was conducted using a KMeans clustering algorithm (scikit-learn version 1.6.1) to identify recurring discussion topics. Results: Total monthly posts steadily increased, with the highest number (2175) in December 2024. Peak posts in descending order were in December 2024, August 2024, and November 2024. Posts were not evenly distributed across the week, with a significant peak on Mondays (χ² = 86.75, p < 0.001) and Poisson regression confirming higher activity early in the week (p = 0.001). Emotional tones fluctuated, with positive sentiments in January and October 2024, and negative sentiments in March and August 2024. KMeans clustering identified five main themes: treatment experiences, community engagement, personal experiences, solidarity, and subreddit gratitude. Manual validation of a random subset of posts demonstrated moderate concordance between automated sentiment classification and human ratings. Conclusions: This study highlights temporal patterns, sentiment dynamics, and thematic structure in online discussions on epilepsy. Social media may offer valuable, real-time insights into patient-centered concerns and community engagement, which can inform healthcare professionals and advocacy groups in supporting individuals affected by epilepsy. Future studies may compare trends of epilepsy discussions across various social media platforms, such as X and Instagram, to further understand online patient experiences. Full article

Ischemic stroke is a leading cause of disability worldwide, marked by profound disruption of the neurovascular unit (NVU), a dynamic grouping of neurons, astrocytes, cerebral endothelial cells (CECs), microglia, pericytes, and oligodendrocytes. While acute stroke interventions such as tissue plasminogen activator and endovascular thrombectomy address reperfusion, they fail to engage the prolonged and cell-specific processes critical for recovery. Extracellular vesicles (EVs), membrane-bound carriers of proteins, lipids, and nucleic acids, have emerged as key modulators of intercellular communication within the NVU. This review synthesizes current evidence on NVU-derived EVs as both regulators and effectors of post-stroke pathology and repair. We highlight the phase-specific roles of EVs in modulating blood–brain barrier (BBB) integrity, thrombosis, angiogenesis, neurogenesis, oligodendrogenesis, synaptic plasticity, and neuroinflammation. This review places special emphasis on how EV cargo reflects the state of their parent cells and how EV-mediated crosstalk orchestrates coordinated neurorestorative responses. We further discuss the dual nature of EVs, their therapeutic potential for stroke, and the methodological challenges impeding clinical translation, including isolation standardization, cell-specific targeting, and regulatory barriers. Thus, adherence to minimal information for studies of extracellular vesicles (MISEV) guidelines is essential to ensure rigor, reproducibility, and transparency. When combined with temporal and cellular specificity, NVU-derived EVs may represent a biomimetic platform for promoting durable recovery in stroke patients. Full article

Facial neuromodulation with botulinum toxin has traditionally been approached from the perspective of wrinkle correction. However, facial expressions primarily arise from coordinated muscular interactions that convey both positive and negative emotional valence. A conceptual framework focused on muscular equilibrium rather than wrinkle severity may therefore offer a more comprehensive, reproducible, and clinically meaningful approach. In this article, we propose the Index of Muscular Equilibrium (IME) Framework, a conceptual model for aesthetic neuromodulation that integrates functional muscle mapping, validated severity scales, and a composite IME score to support personalized treatment planning and outcome assessment. The framework is derived from a narrative review of PubMed-indexed literature on facial muscle activity, emotional expression, and validated clinical assessment tools. It combines a Valence Map to classify positive- and negative-valence muscle groups, a standardized evaluation of static and dynamic hypertonus, a conceptual Plan Score to guide selective neuromodulation, and a feedback-based longitudinal workflow (the IME Loop). Together, these components enable structured assessment of muscular imbalance, integration of established wrinkle severity scales, and translation into individualized, function-oriented treatment strategies, with intended benefits including improved objectivity, reproducibility, and patient communication. By reframing treatment success from the duration of muscle blockade to the duration of expressive harmony, the IME Framework introduces testable constructs for future validation and offers a functional perspective on facial neuromodulation aligned with contemporary affective science. Full article

Background: Septic shock is a leading cause of mortality worldwide, with community-acquired (CA) and hospital-acquired (HA) infections representing distinct clinical entities. The differences in clinical characteristics, immune response profiles, and effects of sepsis treatments between CA and HA septic shock have not been fully elucidated. Methods: This retrospective cohort study included 726 adults with septic shock who were admitted to two ICUs at Modena University Hospital between January 2006 and September 2024. Patients were classified as having CA or HA septic shock based on the origin of the infection. Clinical, microbiological, and immunological data, treatments, and outcomes were analysed. Immune cell dynamics were assessed during the first week after the onset of the shock. Multivariable Cox regression models were used to identify predictors and the effects of treatment on ICU mortality. Results: Among 344 patients with CA and 382 with HA septic shock, those with CA had higher severity scores but lower ICU and in-hospital mortality. Patients with HA exhibited a higher prevalence of multidrug-resistant organisms and more comorbidities. Immunologically, CA survivors showed increasing lymphocyte counts over time, whereas HA survivors mainly demonstrated recovery in T helper cells. Therapeutic strategies were similar between groups; however, continuous renal replacement therapy was more frequent in patients with HA. Neither appropriate empiric antibiotics nor steroids or immunoglobulin therapy independently improved mortality in the multivariate analyses. Conclusions: CA and HA septic shock differ significantly in terms of clinical severity, microbiological aetiology, immune recovery patterns, and outcomes. The lack of mortality benefit from standard treatments highlights the need for personalised management strategies that integrate clinical, immunological, and microbiological data to optimise care in septic shock subpopulations. Full article

As artificial intelligence (AI) continues to expand across clinical environments, healthcare is transitioning from static decision-support tools to dynamic, autonomous agents capable of reasoning, coordination, and continuous interaction. In the context of geriatric medicine, a field characterized by multimorbidity, cognitive decline, and the need for long-term personalized care, this evolution opens new frontiers for delivering adaptive, assistive, and trustworthy digital support. However, the autonomy and interconnectivity of these systems introduce heightened cybersecurity and ethical challenges. This paper presents a Secure Agentic AI Architecture (SAAA) tailored to the unique demands of geriatric healthcare. The architecture is designed around seven layers, grouped into five functional domains (cognitive, coordination, security, oversight, governance) to ensure modularity, interoperability, explainability, and robust protection of sensitive health data. A review of current AI agent implementations highlights limitations in security, transparency, and regulatory alignment, especially in multi-agent clinical settings. The proposed framework is illustrated through a practical use case involving home-based care for elderly patients with chronic conditions, where AI agents manage medication adherence, monitor vital signs, and support clinician communication. The architecture’s flexibility is further demonstrated through its application in perioperative care coordination, underscoring its potential across diverse clinical domains. By embedding trust, accountability, and security into the design of agentic systems, this approach aims to advance the safe and ethical integration of AI into aging-focused healthcare environments. Full article

Background and Objectives: Rapid physiological decline in terminal cancer is frequently accompanied by accelerated skeletal muscle loss. Although bedside ultrasonography (US) is practical and feasible in palliative care settings, the prognostic relevance of short-term muscle change remains unclear. This study aimed to evaluate whether the rate of muscle loss over a 10-day period, assessed by serial ultrasound, is associated with survival duration in terminally ill cancer patients. Materials and Methods: This single-center retrospective cohort study included 87 inpatients with end-stage cancer who underwent bedside ultrasound measurements of the biceps brachii (BB) and rectus femoris (RF). Baseline US was performed within the first three days of admission, followed by a repeat assessment 10 days after baseline (day-10 follow-up ultrasound). Muscle thickness (MT) measurements were normalized by height squared (m²), and 10-day changes were calculated as delta (Δ) indices, defined as baseline minus day-10 values. Because the exposure of interest (Δ) can only be determined after completion of the day-10 assessment, survival timing analyses were anchored to this prespecified landmark. Survival duration was defined as the number of days from the day-10 follow-up ultrasound to death among patients who died within one year. Associations between muscle changes and survival duration were evaluated using correlation analyses and multivariable linear regression adjusted for age, sex, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status, and nutritional risk. The primary analyses focused on survival timing among decedents. Results: Significant muscle loss was observed over the 10-day interval between baseline and 10 days after baseline. Among the 58 patients who died within one year, greater short-term biceps muscle loss, reflected by higher Δ BB muscle thickness index (Δ BB MT-I), was moderately associated with shorter survival duration (r = −0.437, p = 0.0006). In multivariable linear regression analysis, Δ BB MT-I remained independently associated with survival duration (β = −701.19; 95% CI: −1102 to −301; p = 0.0006), whereas RF muscle changes and baseline clinical variables were not statistically significant. Conclusions: Short-term biceps muscle loss assessed by serial ultrasound, as reflected by Δ BB MT-I, is associated with shorter survival duration in terminally ill cancer patients. These findings suggest that dynamic muscle changes, rather than single-time-point measurements, may provide clinically meaningful insight into short-term survival timing. Serial bedside muscle ultrasound may serve as a low-burden adjunct for prognostic communication in palliative care, although prospective time-to-event studies are required for validation. Full article

Choledochal cyst (CC), a congenital biliary anomaly, is associated with recurrent infections, chronic inflammation, and an increased risk of malignancy. Although emerging evidence implicates the biliary microbiome in disease pathophysiology, its developmental dynamics in pediatric CC remain unclear. Using deep metagenomic sequencing and comprehensive functional annotation, this study characterized age-dependent changes in the biliary microbiome of 201 pediatric CC patients stratified into infancy (<1 year), early childhood (1–5 years), and later childhood (5–12 years). We found that while the taxonomic composition and alpha diversity of the microbiota remained conserved across age groups, profound functional remodeling occurred with host development. A core set of microbial species(Bacteroidota, Actinomycetota, Bacillota, and Pseudomonadota) and functional pathways was shared across all ages; however, early childhood (1–5 years) exhibited the greatest number of unique functional genes, metabolic pathways, and carbohydrate-active enzymes, identifying this period as a critical window for microbial metabolic adaptation. Age-specific patterns were also evident in clinically relevant traits: infants (<1 year) harbored the most unique antibiotic resistance and virulence factor genes, whereas the resistome and virulome became more streamlined in older children. These findings establish a paradigm of “taxonomic conservation coupled with functional remodeling” in the CC microbiome and highlight age as a key determinant of microbial community function. This study offers novel insights into the microbial dynamics underlying CC progression and suggests potential age-specific targets for future therapeutic strategies. Full article

Antimicrobial resistance (AMR) in hospital wastewater is a recognized public health concern, yet the dynamics of its emergence remain poorly understood. This study aimed to characterize the quantitative and qualitative changes in the microbial community of a newly built internal medicine intensive care hospital wing following the start of patient treatment. Wastewater samples were collected regularly from eight relevant sites, including seven patient-associated locations within the intensive care ward and the central sanitary sewer where all effluent converged. Culture-based analyses targeted the “ESCAPE-SO” bacterial and fungal groups (“Enterococci”, “Staphylococci”, “Candida”, “Acinetobacter”, “Pseudomonas”, “Enterobacteriaceae”, “Stenotrophomonas”, “Others”). Comparisons were made between a 12-month pre-operation period (only flushing every 72 h to prevent contamination of the drinking water system) and the first 12 months of patient treatment. The results showed a significant increase in mean bacterial concentrations from 53 [0–349] CFU/mL before patient treatment to 8423 [3054–79,490] CFU/mL during patient treatment (p = 0.0224) with a particular focus on Pseudomonas spp. as the dominant genus. Resistance against all four main antibiotic classes of the WHO AWaRe essential “watch” list (carbapenems, third-generation cephalosporins, broad-spectrum penicillin and ciprofloxacin) emerged within the first twelve months and depended on the amount of prescribed antibiotics and the number of patients treated. These findings indicate that hospital activity drives rapid development of antimicrobial resistance in wastewater microbial communities, highlighting the critical role of clinical antibiotic use in shaping environmental resistomes. This study provides quantitative evidence that resistance can emerge within months of hospital operation, emphasizing the need for early monitoring and targeted interventions to mitigate the spread of AMR from hospital effluents into broader environmental systems. Full article

Background: Effective preoperative patient counseling is essential to shared decision-making. In thyroid surgery, patient communication can be complicated by the complex anatomy and variable surgical approaches, which may not be fully conveyed through conventional verbal explanations or schematic drawings. Virtual three-dimensional (3D) thyroid models may provide an intuitive tool to enhance patient comprehension. Methods: We conducted a randomized controlled trial at Peking Union Medical College Hospital with 94 newly-diagnosed thyroid cancer patients scheduled for thyroidectomy. Participants were assigned to either the control group (n = 47), which received preoperative drawing-based counseling, or the intervention group (n = 47), which utilized a virtual 3D model for communication. The Thyroid Navigator app, developed by Kuma Hospital, was used to provide dynamic 3D representation of the thyroid gland, surrounding structures, and potential surgical procedures. After standardized preoperative consultations, patients were surveyed to assess their understanding in pertinent anatomy and postoperative complications. Results: Patients in the 3D model group demonstrated similar correct response rates in lesion localization (p = 0.536) or parathyroid gland recognition (p = 0.071), but significantly higher accuracy in identifying the recurrent laryngeal nerve and the extent of lymph node dissection compared with the control group (p < 0.05). Moreover, comprehension of the causes of major postoperative complications—including hoarseness (recurrent laryngeal nerve injury, p = 0.004), hypocalcemia (parathyroid gland impairment, p = 0.015), and bleeding (inadequate hemostasis, p = 0.008)—was significantly improved in the 3D model group. Conclusions: Use of a virtual 3D thyroid model significantly improves patient comprehension of thyroid anatomy, surgical procedures, and potential complications, thereby enhancing clinician–patient communication. Virtual 3D models represent a practical and cost-effective supplement to conventional counseling in thyroid surgery, offering clear benefits in patient education and shared decision-making. Full article

The oral cavity acts as the anatomical gateway to the respiratory tract, sharing both microbiological and pathophysiological links with the lower airways. Although radiotherapy is a cornerstone treatment for lung cancer, reliable oral microbiome biomarkers for predicting patient outcomes remain lacking. We analyzed the oral microbiome of 136 lung cancer patients and 199 healthy controls across discovery and two validation cohorts via 16S rRNA sequencing. Healthy controls exhibited a significantly higher abundance of Streptococcus compared to patients (p = 0.049, p < 0.001, p < 0.001, respectively). The structure of the microbial community exhibited substantial dynamic changes during treatment. Responders showed enrichment of Rothia aeria (p = 0.027) and Prevotella salivae (p = 0.043), associated with prolonged overall survival (OS) and progression-free survival (PFS), whereas non-responders exhibited elevated Porphyromonas endodontalis (p = 0.037) correlating with shorter OS and PFS. According to Analysis of Compositions of Microbiomes with Bias Correction 2 (ANCOM-BC2) analysis, Akkermansia and Alistipes were nearly absent in non-responders, while Desulfovibrio and Moraxella were virtually absent in responders. A diagnostic model based on Streptococcus achieved area under the curve (AUC) values of 0.85 (95% CI: 0.78–0.91) and 0.99 (95% CI: 0.98–1) in the validation cohorts, and a response prediction model incorporating Prevotella salivae and Neisseria oralis yielded an AUC of 0.74 (95% CI: 0.58–0.90). Furthermore, in small cell lung cancer, microbiota richness and diversity were inversely correlated with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.008, p < 0.001, respectively) and pro-gastrin-releasing peptide (ProGRP) levels (p = 0.065, p = 0.084, respectively). These results demonstrate that lung cancer-associated oral microbiota signatures dynamically reflect therapeutic response and survival outcomes, supporting their potential role as non-invasive biomarkers for diagnosis and prognosis. Full article

Background/Objectives: Elderly cancer patients in perioperative intensive care units represent a highly vulnerable population due to complex medical needs and physiological challenges. In these high-pressure settings, nurses play a crucial role as patient advocates to ensure well-being and person-centered care. However, there is limited understanding of how nurses operationalize this advocacy role for this specific patient group. This study aimed to explore the conditions and strategies guiding nurses in advocating for elderly cancer patients in perioperative ICU contexts. Methods: Using a Grounded Theory approach, six nurses with direct experience in caring for elderly cancer patients in an oncology institution were recruited. Data were collected via in-depth semi-structured interviews, participant observation, and field notes. Analysis followed the constant comparative method and was supported by MAXQDA software to systematically identify codes, dimensions, and categories, highlighting essential elements of nursing advocacy. Results: Advocacy emerged as a central nursing function, serving both practical and ethical imperatives. Conditions activating advocacy included patients’ complex vulnerability, threatening dignity, mitigated by the family’s anchoring role. Institutional barriers, such as professional devaluation and staffing shortages, often hindered advocacy, resulting in moments of “failure to advocate.” Strategies formed a dynamic process: beginning with in-depth knowledge, progressing through communication mediation, and culminating in direct action. Conclusions: This study contributes to the development of a data-driven theory that deepens the understanding of nursing advocacy in perioperative intensive care for elderly cancer patients, offering valuable implications for practice, education, and policy development, ultimately supporting optimized care delivery and improved patient outcomes. Full article