This article aims to identify the debriefing strategies used in realistic simulation (RS) in health education and their impact on students training. This is an integrative literature review, developed based on six methodological steps. The research was carried out in the BVS, Scopus, PubMed, Web of Science, SciELO and LILACS databases, using DeCS/MeSH descriptors and Boolean operators. After screening, 10 articles met the inclusion criteria. The results showed that the most used methods were the structured model, debriefing with reflective feedback and video-based debriefing. These strategies have demonstrated effectiveness in promoting active learning, strengthening clinical reasoning, developing technical and non-technical skills, and increasing self-confidence. Improvements were also observed in psychosocial aspects such as emotional safety and empathy. The analysis revealed that debriefing acts as a fundamental pedagogical tool, promoting significant learning experiences that contribute to the student's development. It is concluded that this last stage of RS is essential and should be conducted in a structured manner, by trained facilitators, with methodologies adapted to the context and needs of students. Investment in teacher training and future studies to evaluate the effectiveness of strategies in the long term are recommended.
Atherosclerosis (AS) is a chronic inflammatory vascular disorder driven by dyslipidemia and characterized by foam cell formation originating from vascular smooth muscle cells (VSMCs). Mitophagy is a critical pathway for the selective clearance of dysfunctional mitochondria and also contributes to macrophage foaming. Tripartite motif-containing protein 65 (TRIM65), a key protein within the TRIM family, plays a significant role in immune and inflammatory responses and is integral to the pathogenesis of AS. In vivo and in vitro models of as were established using ApoE-/- mice fed a high-fat diet and mouse aortic vascular smooth muscle (MOVAS) cells treated with oxidized low-density lipoprotein (ox-LDL), respectively. Results indicated a significant increase in TRIM65 expression in atherosclerotic models. The generation of TRIM65-/-ApoE-/- mice demonstrated that TRIM65 knockdown reduced atherosclerotic plaque burden and lipid accumulation. In vitro experiments revealed that TRIM65 knockdown inhibited the formation of VSMC-derived foam cells while promoting mitochondrial autophagy. Mechanistic investigations showed that TRIM65 facilitates the degradation of key mitochondrial autophagy proteins (e.g., PINK1, Parkin), thereby inhibiting mitochondrial autophagy. This inhibition leads to the accumulation of dysfunctional mitochondria, resulting in excessive ROS generation and exacerbating oxidative stress. By inhibiting mitochondrial autophagy, TRIM65 accelerates the formation of VSMC-derived foam cells, thereby promoting the onset and progression of as. This discovery not only deepens our understanding of the molecular mechanisms of as but also provides theoretical support for positioning TRIM65 as a potential novel therapeutic target for the prevention and treatment of this disease.
Chronic hepatitis B virus (HBV) infection remains a significant global health burden. Although the canonical HBV proteins are well-studied, the pathological roles of HBV spliced variants and their encoded proteins are poorly understood. In this study, we investigate the cancer-promoting potential of hepatitis B doubly spliced protein (HBDSP), encoded by the 2.2 kb doubly spliced variant of HBV, and its underlying mechanism in hepatocellular carcinoma (HCC). In vitro functional assays demonstrated that HBDSP induces epithelial-mesenchymal transition (EMT) and enhances migration and invasion in HepG2 and Huh7 cells. Mechanistically, cellular and molecular approaches revealed that HBDSP enhanced the nuclear translocation of SP1 and ETS1, thereby facilitating their binding to the yes-associated protein (YAP) promoter and activating YAP transcription. Inhibition of YAP using either the pharmacological inhibitor Verteporfin or YAP-specific siRNA effectively abolished HBDSP-induced malignant phenotypes, confirming the essential role of YAP in this process. Notably, these effects were consistently validated in both HBV-replicating HepG2.2.15 cells and HBV-infected HepG2-NTCP cells, further reinforcing the pathological relevance of HBDSP in HBV-driven hepatocarcinogenesis. Taken together, we identify HBDSP as a novel viral effector that facilitates EMT, migration, and invasion in hepatoma cells via transcriptional activation of YAP in an SP1- and ETS1-dependent manner. These findings suggest that HBDSP-mediated activation of YAP may play a role in HBV-driven HCC progression and could be explored further as a potential therapeutic axis, particularly in contexts where spliced HBV variants are prevalent.
Triple Negative Breast Cancer (TNBC), an aggressive type of Breast Cancer (BC) characterized by the loss of expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal growth factor Receptor 2 (HER2) protein. TNBC is quite heterogenous in nature with limited available therapeutic options due to the lack of defined molecular targets. Epigenetic abnormalities have been implicated in the onset, progression, immune escape, and resistance to treatment in TNBC. Important epigenetic modulations, include DNA methylation, histone lactylation, histone modifications, and chromatin remodeling. Global hypomethylation contributes to genomic instability, while promoter hypermethylation inhibits tumor suppressor genes, by dysregulating their expression, thereby promoting uncontrolled proliferation, EMT, metastasis, and immune evasion in TNBC. Targeting epigenetic modulators, have the potential to develop novel therapeutic interventions have been developed and being explored. These epidrugs have proven to be effective in preclinical and clinical trials when used in combination with chemotherapy, immunotherapy, or targeted therapy, reducing drug resistance and aberrant proliferation. Despite of the advancements, challenges like target specificity, precise biomarkers and treatment related toxicity are the major hurdles. The review comprehensively summarized the important epigenetic alterations as well as novel treatment strategies with potential clinical applications in TNBC.
Under the background of rapid urbanization, imbalances and spatial mismatches between the supply and demand of ecosystem services (ES) have become major constraints on regional sustainable development. Accurately identifying ecological compensation areas and establishing scientifically sound compensation standards are critical for alleviating the conflicts between economic development and ecological conservation. This study takes the middle reaches of the Yangtze River urban agglomeration (MYUA) as the study area and focuses on three key ES in 2023-carbon sequestration (CS), air purification (AP), and water purification (WP). Centered on the questions of what to compensate, who should compensate, and how much to compensate, this study conducts a quantitative assessment of ecosystem service supply and demand, a spatial analysis of ecosystem service flows (ESF), and a systematic estimation of ecological compensation standards. The results indicate that: (1) The overall supply-demand matching of ES in the MYUA is relatively good, with the degree of matching ranked as WP > CS > AP; (2) Significant differences exist in the spatial flow characteristics of the three services. The CS forms 16 intercity flow pathways, with transfer distances ranging from 32.51 to 339.40 km. The AP constitutes a flow network composed of 26 pathways, with transfer distances between 22.32 and 445.58 km. The WP exhibits 21 instances of spatial transfer, among which the flow from Changsha to Jingzhou is the largest (640.73 t), while the flow from Xiangtan to Ezhou is the smallest (0.27 t); (3) The total ecological compensation amounts reach 1.411 billion CNY (≈ 0.20 billion USD) for CS, 678 million CNY (≈ 95.50 million USD) for AP, and a relatively lower 7.6002 million CNY (≈ 1.07 million USD) for WP. This study provides a theoretical basis and decision-making support for formulating scientifically grounded ecological compensation policies and promoting coordinated green development in the MYUA.
Obesity is a modifiable risk factor for postmenopausal breast cancer. As obesity-gut microbiome interactions are well known, obesity might also impact tissue-resident microbiome populations as a mechanism promoting breast cancer. Using non-cancerous breast tissue samples, we demonstrated that obesity and aging interact to shift the tissue-resident microbiome in breast cancer patients. Breast tissue from postmenopausal women with obesity displayed a significantly different α-diversity and β-diversity than pre- and postmenopausal women without obesity. At the species level, breast tissue from postmenopausal women with obesity expressed elevated Akkermansia muciniphila abundance when compared with all other groups. A secondary cohort of non-cancerous breast tissue from reduction mammoplasty patients indicated participant body mass index correlates with breast A. muciniphila abundance. Elevated mammary gland A. muciniphila in female MMTV-PyMT mice fed a high-fat Western diet increased tumorigenesis, tumor multiplicity, and oxidative stress markers, and administration of antioxidant N-acetylcysteine reduced A. muciniphila-induced tumorigenesis and redox perturbations. In an orthotopic progression model, mammary gland A. muciniphila in Western diet-fed mice promoted ER+ tumor growth and lung metastases. Taken together, these results suggest obesity and aging interact to enrich breast A. muciniphila abundance, modifying tissue redox balance as a risk factor for obesity-mediated postmenopausal breast cancer.
The escalating demand for ammonia (NH3) as a promising energy vector and essential chemical raw material in both industrial and agricultural applications, coupled with its noxious and caustic properties, has led to significant atmospheric emissions that pose environmental and health risks. Photocatalytic NH3 oxidation over TiO2 is a promising strategy for air purification but is hindered by poor selectivity, often leading to the formation of toxic NOx byproducts due to the complex reaction network involving multiple competing pathways and intermediates. This study addresses this selectivity issue by designing a modified TiO2 photocatalyst through a synergistic defect-dopant engineering approach. Through controlled doping and defect engineering, we demonstrate that N doping and OVs distinctly modulate the reaction mechanism and products' selectivity. Nitrogen doping thermodynamically promotes N2 formation by stabilizing NH2 intermediates and facilitating their selective coupling with NO, whereas OVs kinetically facilitate NH3 and O2 dissociation, promoting superoxide-mediated oxidation, leading to overoxidized products such as NOx and nitrate/nitrite HNOx- species. An optimal N-doped TiO2 catalyst achieves 87% NH3 conversion with 80% N2 selectivity and minimal NOx emission (∼5 ppm), while exhibiting excellent stability over multiple cycles. This work elucidates a defect-dopant strategy that optimizes kinetic and thermodynamic aspects of NH3 oxidation, providing a design principle for selective photocatalytic nitrogen management toward sustainable air purification.
Recent advances in bariatric interventions have introduced innovative surgical and endoscopic techniques aimed at promoting weight loss and improving obesity-related comorbidities. This study compares the effectiveness of various bariatric procedures in managing metabolic conditions and optimizing clinical outcomes. A systematic literature search through January 2025 identified comparative studies, including 16 randomized controlled trials (RCTs) and 39 observational studies (follow-up range: 6-120 months), evaluating diabetes mellitus (DM), hypertension (HTN), dyslipidemia (DLP), and obstructive sleep apnea (OSA) outcomes following bariatric surgery. Secondary outcomes included de novo gastroesophageal reflux disease (GERD) incidence and GERD improvement. Fifty-five studies involving 61,154 patients were analyzed. For DM improvement, one-anastomosis gastric bypass (OAGB) was significantly superior to both Roux-en-Y gastric bypass (RYGB) (OR: 1.92; 95% CI: 1.18-3.13) and sleeve gastrectomy (SG) (OR: 2.47; 95% CI: 1.49-4.09). OAGB and RYGB also showed significantly greater HTN improvement compared to SG (OR: 1.84; 95% CI: 1.20-2.84 and OR: 1.30; 95% CI: 1.14-1.49, respectively). For de novo GERD, ESG (OR: 0.08; 95% CI: 0.01-0.72) and RYGB (OR: 0.29; 95% CI: 0.18-0.48) showed significantly lower odds than SG. For GERD improvement, OAGB (OR: 5.48; 95% CI: 1.52-19.76) and RYGB (OR: 3.82; 95% CI: 2.09-6.97) significantly outperformed SG. P-score rankings placed SADI highest for DM (0.932), OAGB for HTN (0.769) and DLP (0.731), and SASI for both de novo GERD (0.803) and GERD improvement (0.900). OAGB, SASI, SADI, and ESG demonstrate superior efficacy in improving obesity-related comorbidities and GERD outcomes, supporting their consideration as leading options in individualized bariatric care. However, evidence is limited with outcomes heterogenously defined across studies. Future RCTs are needed to provide comparative efficacy between these interventions.
Problematic smartphone use is common among parents. This study examines how parental problematic smartphone use when children are 3.5 years old is prospectively associated with the development of internalizing symptoms at age 5.5. Participants are 315 Canadian parents who reported problematic smartphone use based on a seven-item scale (e.g., I use my phone to escape when I am with my children) when their children were 3.5 years old and and child internalizing symptoms by age 5.5 using the sadness subscale from the NIH toolbox. Control variables include child baseline emotional reactivity, measured using the CBQ-Short form and parenting stress, measured using the Parenting Stress Index (PSI-4). A structural equation model was estimated to assess associations between a parental problematic smartphone use latent factor and child internalizing symptoms. Results indicated a positive association between parental problematic smartphone use at age 3.5 and child internalizing symptoms at age 5.5 (β [95% CI] = 0.23 [0.003; 0.45]; p = 0.047). Our findings indicate that parental problematic smartphone use is associated with increased child internalizing symptoms. These results highlight the importance of considering parental screen media use habits when designing awareness and intervention efforts aimed at promoting healthy child development and well-being.
In the 21st century, the emergence of multidrug-resistant bacteria has become a major concern in human and animal health, promoting the search for sustainable alternatives to antibiotics in aquaculture. Among these, probiotics have shown promising potential to improve fish health and disease resistance. This study evaluates the probiotic potential of Paenibacillus polymyxa SABE1 for application in European seabass (Dicentrarchus labrax) aquaculture. Its functional properties were assessed through in vitro assays, a challenge test against Vibrio parahaemolyticus, and whole-genome sequencing to determine safety and potential risks. Results indicate that P. polymyxa SABE1 exhibits strong antimicrobial activity, adhesion capacity, digestive resilience, and no hemolytic or pathogenic traits. Notably, the challenge assay showed a survival rate of 56.67% in treated fish, confirming its protective effect. Genomic analysis further supported its safety, revealing no relevant antibiotic resistance or virulence factors. Overall, P. polymyxa SABE1 demonstrates strong potential as a safe and effective probiotic candidate, supporting its use as a sustainable alternative to antibiotics in aquaculture.
Although substantial evidence links sweetened beverage (SB) intake to chronic diseases, its association with biological aging and underlying mechanisms remains unclear. This population-based study included 9104 adults aged 18-80 years from the WELL-China cohort. SB consumption was assessed using a validated food frequency questionnaire. Biological age and biological age acceleration (BAacc) were estimated using the Klemera and Doubal method (KDM). After multivariable adjustment, frequent SB consumption was significantly associated with accelerated KDM-derived BAacc, compared with non-consumers (β = 0.29 years, 95% CI: 0.06-0.52). This association was stronger among participants younger than 55 years (P for interaction < 0.05). Gut microbiota was profiled using 16S rRNA gene sequencing. We identified 10 genera significantly associated with the frequent SB consumption, and 56 genera significantly associated with BAacc. Notably, five genera (Allisonella, Lactobacillus, Weissella, Lactococcus, and Bacilli_unclassified) were shared between the two analyses and enriched in both frequent SB consumers and individuals with higher BAacc. Frequent SB consumption is associated with accelerated biological aging, especially among adults younger than 55 years. Shared gut microbial signatures associated with both SB intake and BAacc suggest a potential microbiota-related pathway. These findings support reducing SB consumption as a potential strategy for promoting healthy aging.
The prevalence of obesity and type 2 diabetes mellitus (T2DM) in the older adult population is rising continuously worldwide, with approximately 40% and 29% of individuals affected in this group, respectively. These conditions have a substantial impact on older adults and are associated with reduced quality of life, increased morbidity, functional decline, and cardiovascular disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as an important option for the management of T2DM and obesity. However, special considerations are needed for specific age groups due to risks of adverse effects and increased comorbidity burden. GLP-1 RAs, including tirzepatide, liraglutide, and semaglutide, promote weight loss by suppressing appetite, improving insulin secretion, and delaying gastric emptying. Large clinical trials have supported GLP-1 RAs as an excellent option for reducing glycated hemoglobin and body weight, as well as for reducing major renal and cardiovascular adverse effects; however, evidence in older adults remains limited. Given the health considerations for older adults, weight loss efforts with GLP-1 RAs require cautious approaches, as sarcopenia is a relevant topic in this specific age group. Polypharmacy and side effects also need to be considered when treating an older adult with GLP-1 RA. Overall, GLP-1 RAs represent a valuable and promising treatment option for older adults with T2DM and obesity.
Protein lactylation, a novel post-translational modification utilizing lactate as the substrate, has emerged as a key mechanism linking metabolic alterations to cancer progression. This study aims to investigate the role and underlying mechanism of S100A11 lactylation in gastric cancer progression and metastasis. Lactylome profiling, site-directed mutagenesis, co-IP, cycloheximide chase, ubiquitination assays, and in vitro/in vivo functional experiments were performed to dissect the regulatory effect of S100A11 lactylation. S100A11 was identified as a hyperlactylated protein in gastric cancer tissues, with lysine 27 (K27) and lysine 55 (K55) serving as the primary modification sites. Mechanistically, lactylation at K27 and K55 disrupted the interaction between S100A11 and its E3 ubiquitin ligase FBXW11, thereby inhibiting polyubiquitination and proteasomal degradation of the protein. The K27R/K55R double mutation, which abolished both lactylation and ubiquitination at these residues, resulted in constitutive stabilization of S100A11. The stabilized S100A11 hyperactivated the PI3K-AKT and ERK1/2 signaling cascades and upregulated the downstream oncogenic effectors Cyclin D1 and c-Myc. Functionally, S100A11 stabilization significantly enhanced the proliferation, colony formation, migration and invasion of gastric cancer cells in vitro, and markedly promoted lung metastasis in vivo. Clinically, higher lactylation levels of S100A11 were observed in patients with advanced TNM stages. This study reveals a lactylation-ubiquitination competitive regulatory mechanism that governs S100A11 protein stability, which directly links Warburg effect-derived lactate to oncogenic protein stabilization and metastatic progression in gastric cancer.
Transitioning to practice as a newly graduated registered nurse (NGRN) is becoming increasingly more challenging as our patients and the healthcare environment grow in complexity. Many NGRNs report feeling low confidence levels, increased stress, and a general lack of knowledge about various specialty areas of nursing when entering practice, which can result in poorer patient outcomes and may contribute to increased attrition rates in nursing. Exploring new ways to create positive transitions into practice for NGRNs remains crucial. Targeted experiences, focusing on knowledge gaps, such as in the field of gastroenterology, may enhance learning, increase confidence levels, and improve patient care. For this reason, an innovative Gastroenterology Experience Project (GEP), including targeted simulations and didactic content, was developed and implemented in a transition to practice program for NGRNs. The purpose of the GEP was to enhance NGRN knowledge of the most common gastrointestinal (GI) diagnostic tests and procedures, understand the nurse's role as an effective team member, and promote safe and high quality nursing care before, during, and after GI interventions. This article discusses a unique collaboration between nurses from the education, simulation, and gastroenterology departments and NGRNs participating in a new nurse residency program at a large metropolitan health care system in the Midwest. The implementation of the GEP, as well as quantitative findings and NGRN reflections, will be discussed.
Photoreceptors are highly specialized neurons that depend on continuous membrane renewal and tightly regulated lipid homeostasis to maintain their visual function. Age-associated disruptions of these processes increase cellular stress and contribute to photoreceptor degeneration. Pigment epithelium-derived factor (PEDF) is a potent neuroprotective factor in the retina, and the identification of its receptor, PEDF-R (PNPLA2), has provided key mechanistic insight into how PEDF signaling is coupled to lipid metabolism. The present review examines the molecular and cellular mechanisms underlying PEDF-R function in photoreceptors and the retinal pigment epithelium (RPE). PEDF-R acts as a multifunctional enzyme with phospholipase and lipase activities that link extracellular PEDF binding to intracellular lipid remodeling. Through these activities, PEDF-R has been associated with processes essential for photoreceptor survival such as membrane phospholipid turnover, mitochondrial integrity, calcium homeostasis, and redox balance. In addition, PEDF-R contributes to retinoid metabolism and lipid processing associated with outer-segment renewal in the RPE. We further discuss how disruption of the PEDF-PEDF-R pathway impairs lipid homeostasis, promotes oxidative and inflammatory stress, and increases susceptibility to age-related retinal degeneration. These insights position PEDF-R as a key contributor to photoreceptor homeostasis and a potential therapeutic target for preserving retinal function in aging and disease.
Anxiety disorders pose a considerable burden on public health. While exercise has been increasingly established as a viable strategy for preventing and alleviating anxiety symptoms, the underlying molecular mechanisms of this action remain elusive. We previously conducted an 8-week randomized controlled trial which suggested that exercise not only significantly reduced anxiety levels but also triggered the release of acidic ribosomal protein P2 (RPLP2) from peripheral tissues into the bloodstream. These elevated circulating RPLP2 levels showed an inverse association with anxiety severity in patients, suggesting a potential therapeutic role for the protein. Further experiments in mice confirmed that skeletal muscle-derived RPLP2 exerts its anxiolytic effects by facilitating hippocampal neurogenesis. Mechanistically, RPLP2 facilitates ribosomal localization and increases the efficiency of ribosomal subunit assembly, thereby increasing local protein synthesis and supporting the development and maturation of newly generated neurons. The successful maturation of these neurons, in turn, promotes morphological and functional synaptic plasticity, which is crucial for the integration and functional maturation of newborn neurons into hippocampal circuits. Collectively, our findings reveal a previously unknown muscle-brain axis mediated by RPLP2, offering mechanistic evidence for exercise-induced stress resistance.
Large language models (LLMs) are increasingly applied in radiology, but key challenges remain, including data leakage from cloud-based systems, false outputs, and limited reasoning transparency. This study aimed to develop an open-source, offline-deployable retrieval-augmented LLM (RA-LLM) system in which local execution prevents data leakage and retrieval-augmented generation (RAG) improves output accuracy and transparency using reliable external knowledge (REK), demonstrated in pancreatic cancer staging. Llama-3.2 11B and Gemma-3 27B were used as local LLMs, and GPT-4o mini served as a cloud-based comparator. The Japanese pancreatic cancer guideline, written in English, served as REK. Relevant REK excerpts were retrieved to generate retrieval-augmented responses. System performance, including classification accuracy, retrieval metrics, and execution time, was evaluated on 100 simulated pancreatic cancer cases with CT findings described in English, using non-RAG LLMs as baselines. McNemar tests were applied to TNM staging and resectability classification. RAG improved TNM staging accuracy for all LLMs (GPT-4o mini 61% → 90%, p < 0.001; Llama-3.2 11B 53% → 72%, p < 0.001; Gemma-3 27B 59% → 87%, p < 0.001) and mildly improved resectability classification for GPT-4o mini and Llama-3.2 11B (72% → 84%, p = 0.012; 58% → 73%, p = 0.006), while the improvement for Gemma-3 27B was not evident (77% → 86%, p = 0.093). Gemma-3 27B showed performance comparable to GPT-4o mini. Retrieval performance was high (context recall = 1; context precision = 0.5-1), and local models ran at speeds comparable to the cloud-based GPT-4o mini. We developed an offline-deployable RA-LLM system for pancreatic cancer staging and publicly released its full source code. RA-LLMs outperformed baseline LLMs, and the offline-capable Gemma-3 27B performed comparably to the widely used cloud-based GPT-4o mini.
Veterinary pharmaceuticals often enter into ecosystems through the disposal of unused and expired medicines and animal excreta. Consequently, these substances are emerging as a global threat, posing risks to ecosystems, biodiversity and public health. However, despite the increasing concerns attributed to veterinary pharmaceuticals, there is a lack of empirical data regarding awareness and practices related to ecopharmacovigilance (EPV) among veterinary professionals in Ethiopia. EPV is an emerging discipline focused on the detection, evaluation, understanding and the prevention of the environmental impacts of pharmaceuticals. This knowledge gap highlights the need for evidence-based assessment of veterinary professionals' awareness and practices of EPV in Ethiopia. Therefore, this study aimed to assess veterinary professionals' knowledge, attitudes and practices (KAP) regarding EPV and pharmaceutical waste management. A cross-sectional survey was conducted between January 2024 and May 2025 among 37 veterinary healthcare providers in and around Gondar City. The data were collected using a structured, self-administered questionnaire. Data were analysed using SPSS version 25 through descriptive statistics and chi-square tests to identify associations between socio-demographic characteristics and KAP indicators. The study found that 73% of respondents had never heard of EPV, 78.4% had not received relevant training, and 67.6% reported the absence of pharmaceutical disposal guidelines in their facilities. Although 94.6% acknowledged the harmful effects of improper drug disposal on human and environmental health, only 16.2% were familiar with the term EPV. Knowledge was marginally associated with reading scientific literature (p = 0.084), whereas attitudes were significantly related to prior knowledge (p = 0.001), training (p = 0.001) and reviewing related reports (p = 0.001). Practices were influenced by prior knowledge (p = 0.023) and engagement with literature (p = 0.032). About 40.5% of participants disposed of pharmaceuticals in regular trash, and only 27% returned unused drugs to appropriate authorities. Overall, 62.8% of respondent's demonstrated poor knowledge, 56.8% held negative attitudes, and practices were inadequate. This baseline study reveals low awareness of EPV and poor waste management practices among veterinary healthcare providers. The study shows the urgent need for targeted training, policy enforcement and the integration of environmental education into veterinary curricula in Ethiopia. This is necessary to promote responsible pharmaceutical stewardship and safeguard the environment and public health.
Romosozumab (Rmab) is a potent anti-osteoporosis agent with dual effects on bone resorption and formation. Although superior to alendronate in fracture reduction, cardiovascular safety concerns have been raised. This study compared cardiovascular disease (CVD) incidence between Rmab and other anti-osteoporosis medications (AOMs) using Japan's National Database of Health Insurance Claims. Patients aged  ≥ 50 years initiating Rmab, parathyroid hormone analogues (PTH), denosumab (Dmab), or bisphosphonates (BP) between March 2019 and March 2023 were identified. Outcomes were acute myocardial infarction, ischemic heart disease, and cerebrovascular disease occurring within 570 days of initiation or within 180 days after discontinuation. Patients with prior myocardial infarction or cerebrovascular disease were excluded. Hazard ratios (HRs) were derived from Cox regression with inverse probability weighting using propensity scores. The study included 25,584 men and 236,467 women receiving Rmab; 50,688 and 289,132 on PTH; 50,319 and 460,182 on Dmab; and 232,484 and 1,144,757 on BP. Cumulative incidence of outcomes was highest with PTH, followed by Dmab, BP, and lowest with Rmab. Compared with PTH, adjusted HRs for Rmab in men were 0.49 for acute myocardial infarction, 0.59 for ischemic heart disease, and 0.70 for cerebrovascular disease. Compared with Dmab, HRs were 0.62, 0.62, and 0.59, respectively. Versus BP, HRs were 0.68, 0.74, and 0.72. All HRs were similarly below 1.0 in women. After adjustment for baseline characteristics, no excess incidence of cardiovascular events was observed among patients receiving Rmab compared with those receiving other AOMs.
The immune response against cancer is influenced by the tumor stroma. Carcinoma-associated fibroblasts (CAFs), a significant part of the stroma, are important modulators of the tumour microenvironment (TME). The current study examined the immunomodulatory properties of CAFs isolated from a stage II mouse model of mammary invasive ductal cancer. Based on the expression of surface markers, we described Stage II CAFs and assessed their effects on cytokine release, nitric oxide (NO) generation, and splenocyte proliferation in direct co-culture systems. Class II MHC molecules (I-Ad/I-Ed), FAP-1, CD29, CD90, and CD105 were all expressed by isolated CAFs, indicating the possibility of direct immunological contact. In direct co-culture, CAFs demonstrated two distinct functions: their conditioned medium (CM) had immunosuppressive effects, whereas direct cell interactions promoted splenocyte growth. Additionally, CAFs changed the cytokine milieu, particularly by secreting high levels of TGF-β and PGE₂, and dramatically reduced splenocyte NO generation. COX-2, IDO, and MMP2 were significantly upregulated in CAFs, according to gene expression data. Our results emphasize the potential of Stage II CAFs as a therapeutic target in breast cancer by demonstrating their complex immunomodulatory character, which includes the ability to both stimulate and repress immune responses through cellular contact and soluble factors.