Osteoporosis is a metabolic bone disorder characterized by excessive osteoclast-mediated bone resorption, which is exacerbated by inflammatory and oxidative stress-associated signaling pathways. Although anti-resorptive drugs are used to prevent excessive bone resorption, their long-term use may cause adverse effects, highlighting the need for alternative pharmacological interventions targeting osteoclast differentiation and inflammation-associated signaling. Here, we investigated the anti-osteoclastogenic effects of ent-7β-hydroxy-15-oxokaur-16-en-18-yl acetate (Ent7), an ent-kaurane diterpenoid isolated from Croton tonkinensis, under RANKL-induced and inflammatory conditions using an integrated strategy combining transcriptomic profiling, network pharmacology, and molecular docking. Ent7 inhibited RANKL-induced osteoclast differentiation and bone resorption, accompanied by reduced osteoclastogenic marker expression and NF-κB, p38 MAPK, and Akt signaling. Transcriptomic profiling identified 384 differentially expressed genes, with enrichment of oxidative phosphorylation, phagosome, cell cycle, and osteoclast differentiation pathways. Functional validation further demonstrated alterations in cell-cycle progression, mitochondrial characteristics, and respiratory activity following Ent7 treatment. Ent7 also attenuated LPS-enhanced osteoclastogenesis and bone resorption, suppressing LPS-induced MAPK/c-Fos signaling. Integrated in silico analyses identified ACE as a candidate regulatory molecule associated with Ent7 activity, with a predicted binding energy of -9.3 kcal/mol. Consistently, Ent7 reduced the expression of ACE and its downstream receptor AT1R. Pharmacological inhibition of ACE or AT1R attenuated osteoclastogenesis, supporting the potential involvement of the ACE-AT1R axis in the anti-osteoclastogenic effects of Ent7. These findings provide a mechanistic basis for further evaluation of Ent7 in osteoclast-mediated pathological bone loss by demonstrating that Ent7 suppresses osteoclast differentiation under both RANKL-induced and inflammatory conditions through modulation of osteoclastogenic signaling and cellular processes.

Chronic kidney disease (CKD) is highly prevalent globally and affects approximately 1 in 10 adults, with a prevalence of 10% globally and ∼14.4% in North America. High blood pressure (BP) is one of the most common causes for the development of CKD. Conversely, hypertension occurs more frequently in patients with CKD and is found to be uncontrolled in 60%-80% of these patients. The rates of resistant hypertension are amongst the highest for any patient population, with estimates ranging between 40% and 50%. Deteriorating renal function is associated with increasing risk for co-morbid conditions including cardiac disease and stroke. Appropriate management of hypertension is important in patients with CKD but poses frequent challenges in clinical care with the need to balance the desired BP lowering and ideally reno-protective effects against increased risks for nephrotoxicity and medication side effects. Established therapeutic principles in the context of CKD include renin-angiotensin-aldosterone system (RAAS) blockade using either ACE inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose transport 2 (SGLT-2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (nsMRAs), and glucagon-like-peptide-1 (GLP-1) agonists. Aldosterone dysregulation is emerging as another key driver of persistently uncontrolled BP and deteriorating kidney function, not only through the associated sodium and fluid retention but also through BP-independent effects on endothelial function, inflammatory pathways, tissue fibrosis, and hypertrophic responses. The new drug class of aldosterone synthase inhibitors (ASIs), highly selective agents inhibiting CYP11B2 and thereby reducing circulating aldosterone levels, may offer a novel opportunity to effectively lower BP and reduce organ damage mediated by dysregulated aldosterone. Indeed, recently published data from phase 3 randomized controlled hypertension trials with various ASIs have demonstrated substantial office and ambulatory BP lowering efficacy with an acceptable safety profile. A reduction in albuminuria in early phase 2 trials in patients with hypertension and CKD may indicate reno-protective properties of ASIs. Dedicated outcome trials are ongoing to explore these prospects in detail.

Chemical pollution from rare earth elements (REEs) has emerged as a significant threat to the stability of freshwater ecosystems. Among these elements, europium oxide (Eu2O3) is widely used across various industrial sectors; however, its specific impacts on fish physiology, health, and immune function remain poorly understood. This study aimed to evaluate the effects of Eu2O3 on growth, hepatic markers, intestinal enzyme, systemic immune response, and cytokine expression in African catfish (Clarias gariepinus). Fish were divided into four experimental groups and exposed to Eu2O3 concentrations of 0 (Eu0), 5 (Eu5), 10 (Eu10), and 50 (Eu50) μg/L of water for 28 days. The results revealed a lower doses (Eu5) appeared to stimulate growth, whereas higher doses (Eu10 and Eu50) significantly impaired growth performance, digestive enzymes, and hepatic damage (p < 0.01). High doses of europium (Eu10 and Eu50) significantly suppressed immune function, as shown by lower IgM, IgG, lysozyme activity, and C3 levels (linear effect, p < 0.05). High concentration exposure induced severe oxidative stress levels (ACE, myeloperoxidase, cortisol, glucose, MDA, and nitric oxide), along with a depletion of antioxidant status (TAC, GSH, and SOD) (linear effect, p < 0.05). Compared to the control, the Eu10 and Eu50 groups showed significantly higher levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and significantly lower activities of mitochondrial metabolic enzymes (citrate synthase and malate dehydrogenase) (linear effect, p < 0.05). Histological examination revealed severe tissue damage in the kidneys and intestines of catfish exposed to high concentrations of Eu2O3. Molecular docking analyses suggested that Eu2O3 potentially binds to ATP, cytochrome P450 aromatase, and HSP70, proposing that it potential triggers mitochondrial dysfunction and disrupts metabolic homeostasis. Overall, exposure to elevated concentrations of Eu2O3 causes marked immune dysfunction, impairs antioxidant defenses, damages mitochondrial pathways, and provokes systemic inflammation, ultimately compromising the physiological integrity of C. gariepinus.

This evidence-to-recommendation (EtR) framework underpins the Agency for Care Effectiveness Clinical Guideline (ACG) for bacterial skin and soft tissue infections (SSTIs), providing rationale and justifications for its recommendations on diagnosis and antibiotic prescribing in primary and community care. Based on the Grading of Recommendations Assessment, Development and Evaluation framework, five evidence-based recommendations were developed to guide practitioners in making appropriate decisions on the diagnosis, assessment and management of SSTIs, including cellulitis, erysipelas, impetigo, folliculitis, ecthyma, furuncles, carbuncles and skin abscesses. As SSTIs are a leading indication for use of oral antibiotics in primary care, recommendations focus on principles for prescribing antibiotics for specific bacterial SSTIs, including whether antibiotics are indicated and when to prescribe topical, oral or intravenous formulations. The EtR framework consolidates the evidence and considerations that informed the ACG recommendations, including balance of benefits and risks, certainty of evidence, patient preferences and values, resources and feasibility considerations, and acceptability. The ACG can be found at https://go.gov.sg/acg-ssti.

Background and Aims Colorectal endoscopic submucosal dissection (ESD) is established for large superficial neoplasia, but systemic adverse events remain underexplored. We aimed to assess the frequency, predictors, and outcomes of clinically evident acute kidney injury (AKI) after colorectal ESD. Methods All consecutive colorectal ESDs performed at Limoges University Hospital (2017-2024) within the prospective French ESD Colorectal Cohort (FECCO) were retrospectively analyzed to identify AKI events and related factors. Results Among 1537 patients, the frequency of clinically evident AKI was 1.3% (n = 20). Compared with non-AKI patients, AKI-patients were older (74 vs. 70 years, p = 0.029) and more often receiving angiotensin-converting enzyme (ACE) inhibitors (40% vs. 13.6%, p = 0.003). AKI-patients had larger lesions (100 vs. 55 mm, p < 0.001), longer procedures (181 vs. 55 min, p < 0.001), and higher rates of perforation (35% vs. 10.4%, p = 0.003) and delayed bleeding (36% vs. 5.4%, p = 0.003). ACE-inhibitors (OR 3.96, 95% CI 1.40-9.36) and lesion diameter (OR 1.03, 95% CI 1.02-1.04) were independent predictors of AKI. By the end of follow-up, all patients recovered their baseline renal function. Conclusions AKI after colorectal ESD is rare but clinically relevant. Patients receiving ACE inhibitors and with larger lesions are at higher risk. Careful periprocedural management, including adequate hydration, close monitoring during prolonged or complex procedures, and consideration of ACE inhibitor therapy, may be relevant in this setting.

Ultrasound attenuation coefficient estimation (ACE) has emerged as a quantitative imaging biomarker for noninvasive assessment of hepatic steatosis. A system-independent technique based on spectral normalization, known as the reference frequency method (RFM), was previously proposed to estimate ACE without requiring a well-calibrated reference phantom. Furthermore, incorporating harmonic imaging can significantly suppress reverberation signals. In previous clinical study, RFM has achieved high correlation with MRI-PDFF, demonstrating its potential for clinical application. However, a major challenge of RFM is the presence of oscillations in the frequency power-ratio decay curves (FPDCs), which can distort the linear fitting used to estimate the attenuation coefficient and consequently degrade ACE accuracy. These oscillations arise from constructive and destructive interference among backscattered echoes, resulting in oscillatory fluctuations in the measured power spectrum that propagate into the FPDCs. We propose a transmission scheme combining multiple frequencies and steering angles to mitigate oscillations in the FPDCs. Averaging these FPDCs suppresses the interference-induced oscillations while preserving the attenuation-dependent decay trend, thereby improving linearity and the accuracy of ACE results. In in-vitro experiments using calibrated phantoms (0.5 and 0.76 dB/cm/MHz) demonstrated that the proposed method improved FPDC linearity and ACE accuracy, achieving an R2 of 0.99 and attenuation coefficient estimates of 0.51 and 0.77 dB/cm/MHz, versus an R2 of 0.89 and estimates of 0.56 and 0.70 dB/cm/MHz for conventional RFM. The proposed method also demonstrated superior performance in a pilot patient study (n=15), achieving a stronger correlation with MRI-PDFF (R = 0.89 vs. 0.83) while reducing inter-measurement variability, indicating improved robustness and clinical potential.

Suicide is a leading cause of premature death among US youth, and suicidal thoughts can emerge before adolescence. Adverse childhood experiences (ACEs) are established risk factors for suicidal ideation, while positive childhood experiences (PCEs) and related protective factors may reduce risk, yet no prior synthesis has quantified these associations across independent US pediatric and adolescent samples using effect estimates verified against their source publications. We searched PubMed/MEDLINE, PubMed Central, Centers for Disease Control and Prevention (CDC) publication databases, and reference lists for US-based studies that enrolled children or adolescents younger than 18 years, measured ACEs (cumulative or specific) and/or PCEs or analogous protective factors, reported self-reported suicidal ideation, and published a relative effect estimate with a 95% confidence interval (CI); one report per independent sample entered each pooled analysis. Estimates were pooled with DerSimonian-Laird random-effects models, risk of bias was assessed with the Newcastle-Ottawa Scale, and funnel-plot symmetry and Egger's test were examined for the primary pool but, with fewer than 10 studies, are reported only as exploratory. Eleven reports from 10 independent US samples met the criteria. In the primary meta-analysis of four independent samples, the highest ACE-exposure category (typically three to four or more ACEs) versus no ACEs was associated with substantially higher prevalence of suicidal ideation (pooled relative estimate: 7.19; 95% CI: 5.66-9.14; I-squared = 35%). A graded dose-response was evident, with pooled estimates of 2.78 (95% CI: 2.25-3.43) for the lowest ACE category and 4.60 (95% CI: 3.79-5.58) for intermediate categories, and in two studies reporting per-unit effects, each additional ACE was associated with 60% higher odds of suicidal ideation (pooled odds ratio: 1.60; 95% CI: 1.52-1.69; I-squared = 0%). Protective associations were consistent but not pooled: each additional PCE was associated with 13% lower risk of lifetime suicidal ideation at ages 11-12 (risk ratio: 0.87; 95% CI: 0.82-0.93), and parental monitoring, school connectedness, and family communication were associated with roughly 26-59% lower prevalence of ideation. Risk of bias was moderate for nine reports and high for two. Cumulative ACE exposure thus shows a strong, graded association with suicidal ideation among US children and adolescents, and protective childhood experiences and relationships are consistently associated with lower risk; because the pooled evidence is predominantly cross-sectional and adolescent, prospective preadolescent cohorts remain a priority, and these findings support combined risk- and strengths-based screening and prevention in pediatric and school settings.