Fibroblast growth factor receptor 2 (FGFR2) alterations have emerged as an important targetable oncogenic driver in a biologically distinct subset of biliary tract cancers (BTCs), particularly intrahepatic cholangiocarcinoma (iCCA), alongside other actionable genomic events such as IDH1 mutations, BRAF V600E, HER2 amplification and MSI-H. FGFR2 fusions and mutations define a distinct molecular subgroup whose prevalence varies across geographic regions and etiologic backgrounds such as liver fluke-associated disease. Clinical studies of both reversible and irreversible FGFR inhibitors have demonstrated meaningful activity in FGFR2-rearranged iCCA, while also highlighting a characteristic toxicity profile dominated by on-target hyperphosphataemia. Parallel translational work using cfDNA-based liquid biopsy has mapped a spectrum of secondary kinase-domain mutations that underlie acquired resistance, informing the development of next-generation FGFR2-selective inhibitors (eg, lirafugratinib) and combination strategies with EGFR/ERBB blockade. Collectively, these data underscore the need for comprehensive molecular profiling and innovative umbrella trial designs to optimise targeted therapy in this rare, biologically heterogeneous malignancy.

Background/Objectives: COVID-19 severity is influenced by a complex interplay between host, viral, and environmental factors. Emerging evidence suggests that Neanderthal-derived genetic variants may influence the progression and severity of SARS-CoV-2 infection. This study aimed to evaluate the association between selected Neanderthal-derived variants and COVID-19 severity in the population of the Republic of Srpska, considering relevant clinical, sociodemographic, and lifestyle factors. Methods: This multicentric cross-sectional study included 402 participants, classified as healthy or SARS-CoV-2-positive individuals. A total of 378 COVID-19-positive participants were further stratified according to disease severity and hospitalization status. All individuals were genotyped for the Neanderthal-derived OAS3 rs1156361 (C/T) and LZTFL1 rs35044562 (A/G) variants. Detailed sociodemographic, clinical, and lifestyle data were also collected. Results: A higher frequency of the LZTFL1 rs35044562 AG genotype was observed among hospitalized patients compared with non-hospitalized individuals (36.8% vs. 20.9%; p = 0.005), while the AA genotype was more prevalent among non-hospitalized patients (77.3% vs. 63.2%, p = 0.015). Multivariable logistic analysis showed that carriers of the LZTFL1 AG genotype had a higher chance of hospitalization compared to AA carriers (adjusted OR = 1.372, 95% CI = 0.763–6.383, and p = 0.021). Hospitalized patients more frequently carried the combined CT (OAS3) and AG (LZTFL1) genotypes, supporting a potential synergistic effect. Several sociodemographic factors, including age, sex, education, employment, and urban residence, were also associated with COVID-19 severity, while no significant associations were observed in allele-based analyses. Conclusions: LZTFL1 gene polymorphisms may influence COVID-19 severity, with heterozygote-specific and combined risk effects observed. These preliminary findings are exploratory and require validation in larger cohorts, but may guide future studies and targeted interventions in high-risk groups.

BACKGROUND Fractional flow reserve (FFR)-negative coronary lesions are usually managed medically. Lesion-specific plaque characterization and FFR changes over time remain elusive. AIMS To assess disease progression in FFR-negative lesions over a two-year period using FFR derived from coronary CT angiography (CCTA) (FFRct) and to investigate whether FFR decline over a two-year period is associated with plaque characteristics. METHODS This single-center prospective study included patients undergoing coronary angiography with one or more invasive intermediate lesions (FFR 0.81-0.90) in non-stented, non-culprit coronary arteries. Two years after the index procedure, patients underwent CCTA with FFRct and quantitative plaque analysis. RESULTS We enrolled 131 patients (152 vessels). Two-year follow-up with FFRct and plaque analysis was available in 68 (52 ​%) patients (73 vessels). Compared to invasive FFR at baseline, FFRct at 2y follow-up was significantly lower (median difference -0.06) at vessel level analysis (p ​< ​0.001). FFR declined in 55 (75 ​%) lesions. The 35 study vessels with an FFRct≤0.80 ​at 2-year follow-up had higher total percent atheroma volume (PAV) (41 ​% vs. 23 ​%; p ​= ​0.002) and more high-risk plaque composition, including noncalcified PAV (30 ​% vs. 18 ​%; p ​= ​0.002), and low-attenuation PAV (1.1 ​% vs. 0.7 ​%; p ​= ​0.046) compared to vessels with an FFRct>0.80 (n ​= ​38). Rates of study vessel revascularization in the 131 patients were 6.9 ​% at 2 years and 15.1 ​% after 4.9 years of follow-up after index procedure. CONCLUSIONS Rates of coronary revascularization are substantial in patients with medically managed intermediate lesions. In this selected cohort, an FFRct ≤0.80 ​at two-year follow-up was associated with higher plaque burden and presence of high-risk plaque composition.

Steatosis extends beyond the liver to the pancreas, heart, and skeletal muscle, yet prevailing definitions remain narrowly organ-focused. This narrative review introduces the Metabolic Steatotic Axis (MSA) as a framework that captures the dynamic, bidirectional interactions among these organs, driving systemic metabolic dysfunction. We synthesize evidence linking lipotoxicity, inflammatory signaling, and endocrine cross-talk into a self-amplifying network accelerating insulin resistance, β-cell failure, and cardiometabolic risk. The MSA concept provides a rationale for axis-based staging systems and composite biomarker panels to quantify cumulative disease burden better and refine risk stratification. We highlight phenotypic heterogeneity within MSA stages, the possible hierarchy of organ vulnerability, and the implications for prognosis and therapy. Viewing pharmacological and lifestyle interventions through the MSA lens reframes them as systemic modulators rather than organ-specific treatments, underscoring the need for multi-organ endpoints in clinical trials. Finally, we outline priorities for longitudinal imaging, multi-omics integration, and global harmonization to translate the MSA from a conceptual construct to a clinically actionable paradigm. By unifying fragmented observations into a systemic model, the MSA has the potential to reshape disease classification, therapeutic strategies, and precision medicine in metabolic disorders.

Immigrant populations frequently encounter barriers when accessing healthcare services, potentially affecting patient safety, healthcare utilization, and clinical outcomes. Understanding these barriers is essential for improving equitable and patient-centered care. A systematic review of qualitative and quantitative studies was conducted in accordance with PRISMA 2020 guidelines. PubMed/MedLINE, Embase, Cochrane Library, PsycINFO, EconLit, Web of Science (WoS), and CINAHL were searched from January 2005 to August 2023. Inductive thematic analysis was used to synthesize findings across studies. The review was not prospectively registered, included only English-language studies, and relied predominantly on qualitative evidence. Heterogeneity across study designs and healthcare settings may limit generalizability. The authors received no external funding for this study. Three interconnected themes consistently emerged: limited transcultural competence, language barriers, and discrimination in healthcare. Inadequate cultural competence was associated with communication difficulties and reduced care effectiveness. Language barriers contributed to miscommunication, delayed care, and increased healthcare utilization. Experiences of discrimination were linked to reduced trust in healthcare systems and poorer patient engagement. These factors negatively influenced patient safety, satisfaction, and clinical outcomes. Immigrant patients face persistent and interrelated barriers to healthcare access. Strengthening culturally responsive care, improving access to professional interpreter services, and addressing discriminatory practices are essential to improving patient safety, satisfaction, and clinical outcomes. Future research should evaluate targeted interventions aimed at improving communication, cultural competence, and healthcare equity.

BACKGROUND Minimally invasive surgery is rapidly expanding globally, yet there is insufficient knowledge of how to scale this technology safely and equitably across diverse health systems. We aimed to identify health-system factors associated with safe implementation of minimally invasive surgery globally, using minimally invasive cholecystectomy as a tracer procedure. METHODS We conducted a multicentre, prospective cohort study of consecutive adults undergoing cholecystectomy between July 31 and Nov 19, 2023, in 1218 hospitals across 109 countries. Data were collected by more than 10 000 health-care workers using a core measurement set mapped to the WHO Health System Building Blocks and the Global Patient Safety Action Plan. The primary outcome was 30-day procedure-specific complications, with multilevel logistic regression used to examine associations between health-system features and patient outcomes. This study is registered on ClinicalTrials.gov (NCT06223061). FINDINGS Among 52 187 included patients, the adjusted procedure-specific complication rate varied 40-fold between hospitals, from 0·3% in the lowest risk quintile to 12·1% in the highest risk quintile. Despite large structural differences across income groups in access to minimally invasive surgery, diagnostics, and emergency services, country income level was not independently associated with complication rates (adjusted odds ratio [OR] 0·81 [95% CI 0·59-1·10] for upper-middle income vs high income and 0·99 [0·70-1·39] for lower-middle income or low income vs high income). Three modifiable hospital-level factors were strongly associated with safer outcomes: establishment of local simulation-based training facilities (adjusted OR 0·78 [0·71-0·86]; p<0·0001), adoption of intraoperative safety and communication strategies (0·87 [0·79-0·96]; p=0·0046), and on-site CT diagnostics (0·79 [0·65-0·97]; p=0·0220). Training facilities showed the greatest benefit in hospitals with limited infrastructure and an inexperienced workforce: the number needed to treat to prevent a procedure-specific complication was 21 (95% CI 14-35; p<0·0001). INTERPRETATION Safe implementation of minimally invasive surgery varies widely worldwide but is not defined by national income level; differences in outcomes reflect the ability of health systems to adopt and safely deploy new surgical techniques. We identified for the first time that the presence of local simulation-based training facilities is independently associated with improved patient outcomes. Simulation appears to be fundamental to the safe delivery of minimally invasive surgery, particularly in resource-constrained settings. Together with safety systems and diagnostic capacity, these findings offer actionable targets for health systems seeking to equitably scale up essential surgical technologies. FUNDING NIHR Global Health Research Unit and Wellcome Leap SAVE Programme.

Introduction: Rescue stenting (RS) is a recognized bailout strategy following failed endovascular thrombectomy (EVT) for acute ischemic stroke (AIS). First-line stenting (FLS) has emerged as a potential alternative to avoid vascular injury and improve outcomes. However, direct comparisons between these strategies remain limited. Methods: We conducted a comparative analysis of FLS and RS using data from the RESISTANT registry, an international, multicenter, retrospective cohort of AIS patients who received intracranial stenting during EVT from 2016 to 2023. Patients were categorized by stenting strategy: FLS (stent placed without prior thrombectomy) or RS (stent placed after failed thrombectomy). The primary effectiveness outcome was functional independence (modified Rankin Scale [mRS] 0–2) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage (sICH). Propensity score inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences. Results: Among 827 patients, 723 were in the RS cohort and 104 in the FLS cohort. Compared to RS, FLS patients more often had diabetes (46.2% vs. 35.2%, p =0.03), prior stroke (46.2% vs. 25.3%, p <0.001), prior antiplatelet use (50.0% vs. 27.7%, p <0.001), and known ICAS (28.8% vs. 6.0%, p <0.001). They also had lower baseline NIHSS scores at presentation (median 8 vs. 14, p <0.001) and shorter onset-to-recanalization times (median 363 vs. 392 min, p =0.006). After IPTW adjustment, functional independence was similar between groups (OR=0.64; 95% CI 0.38–1.07), as was the risk of sICH (OR=0.93; 95% CI 0.34–2.59). No significant differences were observed in secondary outcomes including successful reperfusion, mortality, or procedural complications. Outcomes were similar in both the anterior circulation subgrou (n=589; functional independence: OR=0.62; 95% CI 0.60–1.25; sICH: OR=0.81; 95% CI 0.30–2.18) and the posterior circulation subgroup (n=234; functional independence: OR=0.82; 95% CI 0.32–2.10; sICH: OR=0.81; 95% CI 0.30–2.18). Conclusion: FLS and RS strategies during EVT for AIS demonstrated comparable safety and efficacy. Prospective, randomized trials are needed to better define optimal treatment approaches.

Objective: The objective of this study is to compare the analgesic effects of functional magnetic stimulation (FMS) and interferential current therapy (IFC) in patients with knee osteoarthritis (KOA) before and after treatment. Methods: This prospective pilot study included 30 patients with KOA, who were randomly assigned to two groups: FMS (n = 15) and IFC (n = 15). Both groups received 20 treatment sessions over four weeks. Pain intensity was assessed using the visual analog scale (VAS) pre- and post-treatment. Non-parametric statistical tests were applied due to the small sample size and non-normal distribution of the data. Results: In the FMS group, the median VAS score decreased significantly from pre-intervention (Me = 7.0; IQR, 5.0-7.0) to post-intervention (Me = 2.0; IQR, 1.0-2.0), with z = −3.43, p < 0.001. In the IFC group, there was also a significant decrease in the median VAS score from pre-intervention (Me = 7.0; IQR, 5.5-8.0) to post-intervention (Me = 5.0; IQR, 4.0-6.0), z = −3.47, p < 0.001. The Mann-Whitney U test demonstrated a statistically significant difference; the median ΔVAS was significantly higher in the FMS group (Me = 4; IQR, 3.5-6.0) than in the IFC group (Me = 2; IQR, 1.0-2.0) (U = 45, Z = −4.576, p < 0.001). Conclusion: FMS may be a more effective non-invasive treatment option for pain reduction in patients with KOA compared with IFC.

Pannexins are transmembrane glycoproteins that share structural and functional similarities with the gap junction proteins innexins and connexins. They play a critical role in paracrine and intracellular signalling, including purinergic signalling via the release of extracellular ATP. The role of pannexins in renal function and the pathophysiology of renal diseases is being intensely studied. However, there are no data on the subcellular localization of pannexin 1 expression in the rat kidney. We studied the distribution of pannexin 1 in the rat kidney, combining light microscopy with immunofluorescent immunohistochemistry and transmission electron microscopy with immunogold pannexin labelling. We found strong expression of pannexin in glomerular podocytes, proximal tubules and collecting ducts; moderate expression in the endothelium of glomerular and peritubular capillaries; thin descending and thick ascending limbs of the loop of Henle; and weaker pannexin 1 expression in the distal tubular epithelium. We described the detailed ultrastructural localization of pannexin 1 expression. This is the first study describing the ultrastructural distribution of pannexin 1 in the rat kidney, one of the most used preclinical models in renal physiology and pathology research. These results provide previously missing data on the precise distribution of pannexin 1 in the rat kidney, which is a prerequisite for a proper understanding of its role in renal physiology and pathophysiology.

In this study, a model was developed to calculate the power required for the circumferential cutting of solid wood in the longitudinal direction, considering the relevant technological parameters and mechanical properties of the wood. Based on measurements of different combinations and using the Response surface method (RSM) and Central composite design (CCD), a model was created that, in its derived version, considers the cutting width and depth, the diameter and speed of the tool, the number of cutting edges and sharpness of the cutting edge, the feed rate of the workpiece, and the density and moisture content of the wood. The model can be used to calculate the cutting power of various tree species with densities ranging from 400 to 700 kg/m3, moisture contents from 8 to 16%, and a wide range of cutting-edge sharpness, from a sharp cutting edge with a tip radius of 5 µm to a blunt cutting edge with a tip radius of 35 µm. The model is designed for a rake angle of 20°, the value most frequently used in practise. ANOVA analysis was used to determine the suitability of the model, which is highly significant with an R2 value of 0.93 and an average deviation of the calculated values from the measured values of 8.8%. The model is robust and therefore useful in the wood industry for predicting energy consumption in the processing of solid wood.