The clinical benefit of combining leflunomide (LEF) with tumor necrosis factor inhibitors (TNFi) in psoriatic arthritis (PsA) remains uncertain. We aimed to evaluate the efficacy and treatment durability of LEF-TNFi compared with non-LEF regimens (predominantly methotrexate (MTX)-TNFi and TNFi monotherapy). This retrospective cohort included 492 biologic-naive PsA patients initiating TNFi (2003-2020): LEF-TNFi (n = 85) versus non-LEF (n = 407). Multiple imputation addressed missing data, and propensity score matching (7 covariates; caliper 0.2 standard deviations of the logit-propensity score) addressed confounding by indication. Longitudinal outcomes were analyzed using linear mixed-effects models; treatment modification was evaluated via Cox models. Reasons for treatment modification were examined descriptively using a competing risks framework. Substantial baseline imbalances (23 of 36 variables with standardized mean difference > 0.10) were eliminated by propensity score matching (0 of 7 matching covariates with SMD > 0.10; 96.9% of LEF patients retained). Post-adjustment, longitudinal disease activity trajectories did not differ significantly between groups (time-by-treatment interactions: Disease Activity Score in 28 joints (DAS28), p = 0.862; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), p = 0.308). Overall treatment modification rates were similar (propensity score-matched hazard ratio (HR) = 1.16; 95% confidence interval (CI), 0.53-2.51; p = 0.709). Descriptively, LEF patients were more frequently subject to treatment modification for remission (10.6% vs. 5.9%) and less frequently for inefficacy (5.9% vs. 11.1%), although cause-specific hazard ratios did not reach statistical significance. After propensity score adjustment, LEF-TNFi showed no detectable difference in disease activity trajectories or overall treatment persistence compared with MTX-TNFi and TNFi monotherapy. However, LEF-TNFi modifications were predominantly driven by achieved remission rather than inefficacy. Keypoints • Propensity score-adjusted analyses revealed no detectable difference in disease activity trajectories between the LEF-TNFi, MTX-TNFi, and TNFi monotherapy groups in psoriatic arthritis. • Competing risks analysis showed that LEF modifications were driven by remission rather than inefficacy, a clinical distinction obscured by standard composite endpoints. • These hypothesis-generating findings suggest that LEF may be a viable alternative to MTX as concomitant csDMARD therapy with TNFi in PsA.
To evaluate the efficacy and safety of prophylactic mesh reinforcement (PMR) at the closure of emergency midline laparotomy (EML), with a pre-specified subgroup analysis of contaminated and dirty wounds (CDC class III-IV). PRISMA 2020-compliant review (PROSPERO CRD420261324766; OSF 10.17605/OSF.IO/ZX2BG; amendments registered before data extraction). PubMed/MEDLINE, Embase, Cochrane CENTRAL, Scopus and Web of Science were searched (January 2015-March 2026). RCTs and comparative cohort studies reporting incisional hernia (IH) at ≥ 12 months were eligible; bias was assessed with ROB-2/ROBINS-I. Random-effects meta-analysis used the REML estimator with Hartung-Knapp-Sidik-Jonkman correction. A pre-specified Borenstein interaction test compared CDC class I-II with III-IV; trial sequential analysis (TSA) and GRADE were applied. Five studies (4 RCTs; 1 cohort; n = 617) were included. PMR was associated with a reduction in IH (pooled OR 0.221, 95% CI 0.122-0.402 [Knapp-Hartung]; 0.101-0.483 under the conservative truncated variant; I2 = 0%); because control-arm event rates exceeded 10%, this corresponds to an approximate RR of ~ 0.36 (0.28-0.38). The RCT-only analysis was concordant (OR 0.179, 95% CI 0.074-0.435). TSA gave an accrued information size of 617 versus a required ~ 151 (409%), interpreted only as numerical sufficiency, not firm evidence. The CDC interaction was non-significant and underpowered (z = 0.327, p = 0.743). Seroma was significantly increased (k = 4; OR 3.980, 95% CI 1.924-8.234; 1.06-14.94 under the conservative variant), whereas deep SSI was non-significant and underpowered (OR 0.991). LOW to VERY LOW. PMR at EML closure was associated with a consistent IH reduction across CDC classes; however, contaminated-wound evidence is sparse, the subgroup interaction is exploratory, non-significant and underpowered, and the safety profile - particularly deep SSI - remains uncharacterized. Seroma was significantly increased. Given LOW-VERY LOW certainty, these hypothesis-generating findings should not change practice and support an adequately powered multicentre RCT in CDC class III-IV wounds. PROSPERO CRD420261324766 (registered 23 February 2026); OSF Registries https://doi.org/10.17605/OSF.IO/ZX2BG .
Competing risk is a common phenomenon when dealing with time-to-event outcomes in biostatistical applications. An attractive estimand in this setting is the "number of life-years lost due to a specific cause of death". It provides a direct interpretation on the time-scale on which the data is observed. In this paper, we introduce the causal effect on the number of life years lost due to a specific event and give assumptions under which the average treatment effect (ATE) and the conditional average treatment effect (CATE) are identified from the observed data. Semiparametric estimators for the ATE and a partially linear projection of CATE, serving as a variable importance measure, are proposed. These estimators leverage machine learning for nuisance parameters and are model-agnostic, asymptotically normal, and efficient. We give conditions under which the estimators are asymptotically normal, and their performance is investigated in a simulation study. Lastly, the methods are implemented in a study concerning the response to different antidepressants using data from the Danish national registers.
Infertility has long been a major health concern worldwide, with male infertility accounting for approximately half of all cases. In recent years, increasing evidence has shown that long non-coding RNAs (lncRNAs) are involved in the regulation of spermatogenesis. LncRNA AK015322 is a testis-specific lncRNA that is highly expressed in testicular tissue. Previous studies have demonstrated that lncRNA AK015322 promotes the proliferation of spermatogonial stem cells (C18-4) in vitro; however, its role in spermatogenesis in vivo remains unclear. To investigate the effects of lncRNA AK015322 gene knockout on spermatogenesis in male mice. LncRNA AK015322 knockout mice (C57BL/6J) were generated using CRISPR/Cas9 technology. Computer-aided sperm analysis was performed to evaluate sperm parameters in knockout mice. In addition, transcriptome sequencing was conducted to identify potential regulatory genes and signaling pathways associated with lncRNA AK015322. Compared with wild-type mice, lncRNA AK015322-deficient mice exhibited delayed epididymal development, increased sperm morphological abnormalities, and significantly reduced sperm motility. Transcriptome sequencing of testicular tissues identified 98 significantly upregulated genes and 109 significantly downregulated genes in knockout mice. Gene ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses indicated that lncRNA AK015322 may be involved in pathways such as the Hippo signaling pathway and androgen response. Differentially expressed genes were further validated by RT-qPCR. LncRNA AK015322 plays an important role in spermatogenesis, and its deletion leads to impaired sperm function and delayed epididymal development in mice.
Rush immunotherapy (RIT) accelerates the induction phase of allergen-specific immunotherapy treatment (ASIT) by administering incrementally increasing allergen doses over a single day. This approach reduces the time required to maintenance dosing. Safety information in cats with atopic skin syndrome (FASS) remains limited. The objective of the study was to evaluate the safety of RIT in cats with hypersensitivity disease compatible with FASS and to describe the frequency and nature of adverse events. Forty-seven client-owned cats that underwent RIT. A multicentre medical record review from 2019 to 2024 was performed to identify cats that met at least six of 10 criteria for non-flea-induced hypersensitivity dermatitis and were therefore considered consistent with a diagnosis of FASS. All included cats received documented flea prevention and underwent elimination diet trials. Data collected included signalment, medical history, concurrent medications, RIT protocol details, monitoring findings and follow-up communication. Adverse events (AEs) were recorded. In three of 47 cats (6.4%), AEs were observed including tachypnoea, behavioural distress and increased pruritus. In one cat, RIT was discontinued before protocol completion. All affected cats transitioned to maintenance ASIT without recurrence of AEs. Rush immunotherapy appears to be safe in cats with FASS when performed with clinical monitoring. Adverse events were infrequent, mild and self-limiting, supporting use of accelerated induction protocols in appropriately selected patients.
Hip fracture is the most severe complication of osteoporosis. We followed up patients with hip fracture for up to 7 years. Compared with the general population, the overall mortality rate ratio was approximately 9.27 over the follow-up period. Our findings justify the need for urgent improvement of osteoporosis and hip-fracture care. Hip fracture is the most severe complication of osteoporosis, being associated with substantial morbidity, loss of independence, and increased long-term mortality. Data on excess mortality after hip fracture in the population from Eastern Europe is very limited. The objective of the study is to quantify excess mortality after hip fracture by comparing observed with expected mortality derived from age-specific population data for the largest urban region in Romania. We performed a longitudinal observational cohort study including patients hospitalized with hip fracture followed longitudinally up to 7 years after the fracture. A total of 1977 hip fracture patients (1452 women) aged ≥ 40 years were included. Between 2018 and 2024, 1460 deaths occurred (overall mortality 73.85); the overall crude mortality rate in the cohort was 215.6 per 1000 person-years. Compared with the general population, the overall age-specific mortality rate ratio (RR) was approximately 9.27 over the follow-up period. Cohort crude mortality rates were highest in the first post-fracture year and then decreased but remained elevated all across follow-up with overall annual cohort-to-population RRs of 5.74 to 18.10. In univariate Cox regression analyses, female sex was associated with a lower risk of mortality (HR 0.84, 95% CI 0.75-0.94, p = 0.002), while conservative management was associated with a markedly increased risk of death compared with surgical treatment (HR 1.95, 95% CI 1.72-2.21, p < 0.001). In multivariate Cox proportional hazards analysis, conservative management remained independently associated with an increased risk of all-cause mortality (HR 2.01, 95% CI 1.77-2.28, p < 0.001), female sex remains independently associated with improved survival (HR 0.67, 95% CI 0.60-0.76, p < 0.001), and also increasing age is a strong independent predictor of mortality (HR 1.33, 95% CI 1.28-1.37, p < 0.001). Hip fracture is associated with a high and lasting mortality burden in Romanian patients. These findings justify the need for urgent improvement of osteoporosis care and hip fracture systems, aiming to improve survival and quality of life for this patient population.
Several studies have explored the use of deep learning (DL) algorithms based on fundus photography (FP) and optical coherence tomography (OCT) for the detection of glaucomatous optic neuropathy (GON). However, high-quality evidence regarding their diagnostic accuracy remains insufficient. Therefore, this study systematically evaluated the diagnostic performance of DL algorithms for GON detection and compared their accuracy with that of clinical experts to inform the development and optimization of intelligent diagnostic systems. PubMed, the Cochrane Library, Embase, and Web of Science were systematically searched until May 28, 2026. The methodological quality of included studies was assessed using the QUADAS-2 tool. Meta-analyses were conducted based on validation datasets, and subgroup analyses were performed according to imaging modality. A total of 30 eligible studies were included, of which 24 were incorporated into the meta-analysis. For DL algorithms based on FP, the pooled sensitivity (SEN) and specificity (SPC) for GON detection were 0.92 (95% CI: 0.89-0.94) and 0.92 (95% CI: 0.89-0.95), respectively. The pooled positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 11.9 (95% CI: 8.3-17.0) and 0.09 (95% CI: 0.06-0.12), respectively. For clinical experts diagnosing GON using FP, the pooled SEN, SPC, PLR, and NLR were 0.89 (95% CI: 0.78-0.95), 0.92 (95% CI: 0.85-0.96), 10.7 (95% CI: 5.3-21.5), and 0.12 (95% CI: 0.05-0.26), respectively. For DL models based on OCT, the pooled SEN, SPC, PLR, and NLR were 0.87 (95% CI: 0.80-0.92), 0.91 (95% CI: 0.86-0.94), 9.5 (95% CI: 6.3-14.2), and 0.14 (95% CI: 0.09-0.22), respectively. Likelihood ratios presented in the nomogram were rounded to integers to facilitate rapid clinical interpretation. DL models based on FP and OCT demonstrated diagnostic accuracy comparable to that of clinical experts in identifying GON, with FP-based models showing a tendency toward higher SEN. However, in the current application of DL for the detection of glaucomatous optic neuropathy, the generation of validation datasets relies predominantly on internal validation. Although the diagnostic performance of these models is not inferior to that of clinical experts, the results should not be interpreted with undue optimism, and a cautious attitude should be maintained.
The presence of naturally occurring radionuclides in coastal groundwater constitutes a significant public health risk, especially in areas susceptible to hydrological variability. This research applies multivariate statistical methods, including principal component analysis and hierarchical cluster analysis, alongside the PHREEQC thermodynamic model to elucidate the mechanisms governing the mobility of naturally occurring radioactive materials (NORM), specifically gross alpha and beta activity, in a tropical coastal aquifer. Examination of 44 groundwater samples collected over two seasons indicated that more than half exceeded the national guideline for gross alpha activity (0.1 Bq/L). The results indicate that mildly acidic and reducing (anaerobic) conditions facilitate the reductive dissolution of iron and manganese hydroxides. The reductive dissolution of Fe/Mn oxides destabilizes the mineral structures that previously acted as sorptive barriers, thereby releasing trapped radionuclides directly into the groundwater. Additionally, this mobilization is synergistically influenced by competitive ion exchange mechanisms. PHREEQC modeling further identifies a potential iron "lock/release" mechanism: at mildly acidic conditions (mean pH 5.36-5.39), ferrihydrite precipitation is inhibited, maintaining elevated radionuclide mobility. Conversely, as pH increases (up to 7.32), the system approaches supersaturation (saturation index, SI > 0), promoting co-precipitation and resulting in a more than 31-fold decrease in alpha activity during the rainy season (from 0.405 to 0.013 Bq/L). In contrast, beta-emitting radionuclides are less affected by iron-related processes and are predominantly influenced by dilution, with a reduction of approximately threefold (from 0.358 to 0.109 Bq/L). These findings establish a scientific basis for developing cost-effective water treatment approaches, such as aeration combined with pH adjustment, to simultaneously remove heavy metals and alpha radioactivity from tropical coastal aquifer systems.
Global warming has increased the risk of vector-borne diseases, leading to more widespread pesticide use. While health effects of occupational or agricultural pesticide exposure are well documented, evidence linking residential pesticide use to mortality remains limited. We examined the association between residential pesticide exposure in U.S. adults, urinary pesticide metabolites, and both all-cause and cancer-specific mortality to assess the risks of household pesticide use. Data were obtained from the National Health and Nutrition Examination Survey (NHANES). Weighted multivariable Cox regression estimated hazard ratios (HRs) for residential pesticide exposure and mortality. Mediation analysis evaluated the role of urinary metabolites. The dataset was divided into training and validation sets, and three predictive models were developed using machine learning. The study included 21,466 adults. Compared to unexposed participants, those reporting residential pesticide exposure had HRs of 1.444 (95% CI, 1.239-1.683) for all-cause mortality and 1.375 (95% CI, 1.011-1.870) for cancer-specific mortality. Urinary levels of N,N-diethyl-meta-toluamide and N,N-diethyl-3-hydroxymethyl benzamide statistically mediated 20.51% and 19.01% of these risks. All models showed strong predictive performance, with AUC values > 0.8 in both training and validation sets. Residential pesticide exposure may be associated with an increased mortality risk, partially mediated by urinary metabolite levels. Limiting unnecessary household pesticide exposure may help reduce potential health risks, while the predictive model developed in this study may support future risk stratification and the identification of individuals at higher risk, pending external validation.
Non-small cell lung cancer (NSCLC) with KRASG12C mutation is associated with poor prognosis and resistance to standard therapies. Sotorasib, a KRASG12C tyrosine kinase inhibitor, has shown clinical efficacy, yet its interaction with different irradiation modalities remains unclear. This study aimed to evaluate the potential radiosensitizing effect of Sotorasib in such mutated cells exposed to X-rays or carbon-ion (C-ions) irradiation. Two human NSCLC cell lines (H358, KRASG12C; and A549, KRASG12S) were treated with Sotorasib alone or in combination with X-rays or C-ions irradiation (1-8 Gy). Cell viability, clonogenic survival, and sphere-forming ability and cytokines were assessed. Sotorasib alone specifically reduced the clonogenic capacity of H358 cells to ~ 30% while no effect was observed with A549 cells. Interestingly, Sotorasib combined with X-ray irradiation decreased clonogenic survival compared with either treatment alone, without evidence of synergy. In contrast, a synergistic effect was observed with C-ions in H358 cells (β = -0.36, 95% CI [- 0.52 to - 0.20], p < 0.001; enhancement ratio = 4.21 at SF2). C-ions irradiation alone markedly reduced sphere formation in both cell lines, whereas sotorasib showed no additional impact. GM-CSF expression was downregulated with sotorasib alone while IP-10 was upregulated when H358 cells were irradiated with sotorasib, suggesting an immune-specific modulatory response. A specific radiosensitization of KRASG12C -mutated NSCLC cells was observed when associating Sotorasib with C-ions. This represents the first evidence of synergistic enhanced cytotoxicity from combining KRASG12C inhibition with high-LET radiation. These findings support further in vivo and translational studies exploring C-ions therapy as a promising strategy for KRASG12C-mutated NSCLC.
FILOSOPHY (NCT04871919) and PARROTFISH (NCT05323591) are ongoing, prospective observational European phase 4 studies of filgotinib in patients with rheumatoid arthritis (RA) in a real-world setting. We report the study design, baseline characteristics, and interim results for disease activity measures, patient-reported outcomes (PROs), and treatment persistence up to 6 months and safety up to 24 months. Eligible patients had moderate to severe RA and were prescribed filgotinib for the first time in daily practice. In this interim analysis, measures include the proportion of patients achieving low disease activity (LDA), according to Disease Activity Score for 28 joint count using C-reactive protein (DAS28-CRP) or Clinical Disease Activity Index (CDAI), and the proportion achieving a clinically meaningful change from baseline in visual analog scale (VAS) pain (≥ 10 mm reduction) and in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score (≥ 4.0 increase). Treatment persistence was estimated using the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) are reported. From May 2021 to April 2025, 1431 patients initiated filgotinib treatment; 93.0% had completed at least 6 months of follow-up (median follow-up 706 days). Improvements in DAS28-CRP and CDAI occurred from month 1. By month 6, DAS28-CRP ≤ 2.6 was reported for 58.1% (494/850) of patients and CDAI remission for 25.7% (221/859). The proportion with LDA was 71.4% (607/850) based on DAS28-CRP and 69.8% (600/859) based on CDAI. The proportion with a clinically meaningful change from baseline in VAS pain and FACIT-Fatigue score was 44.1% (178/404) and 43.8% (176/402), respectively, at week 1, increasing to 69.6% (227/326) and 62.5% (202/323), respectively, at month 6. Treatment persistence (95% CI) at month 6 was 84.0% (82.0, 85.8). Up to month 24, the exposure-adjusted incidence rates per 100 patient-years of exposure (95% CI) of any TEAEs and serious TEAEs were 89.8 (84.1, 95.8) and 9.4 (8.0, 10.8), respectively. Interim data from FILOSOPHY/PARROTFISH showed improvement of disease activity from month 1 and PROs from week 1, high treatment persistence at 6 months, and no new safety signals. These findings continue to support the safety and effectiveness of filgotinib in daily clinical practice. ClinicalTrials.gov: NCT04871919 (2021-04-29), NCT05323591(2022-04-05).
The interplay between glymphatic function and sleep quality is crucial for brain health and cognitive longevity in late adulthood. Beyond chronological age, whether brain age has specific effects on the associations between glymphatic function, sleep quality, and cognition are understudied in cognitive unimpaired adults. Structural and diffusion magnetic resonance imaging (MRI) data from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) project (N = 582, age range 18-87 years) were used to calculate brain age metrics and the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index. Brain age metrics comprised estimated brain age and the brain predicted age difference (brain-PAD). Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Cognitive assessments included accuracy, reaction time, intraindividual variability of reaction time, and fluid intelligence. Leftward asymmetry of the DTI-ALPS index was consistently observed across brain age-specific groups. The brain-PAD score was significantly correlated with a lower left DTI-ALPS index. Adults with a positive brain-PAD score exhibited a robust correlation between DTI-ALPS indices and sleep quality features, whereas those with a negative brain-PAD score showed a reliable correlation between DTI-ALPS indices and cognition. Mediation analyses further revealed that the relationship between left DTI-ALPS index and sleep efficiency was mediated by brain age. This study provides the first demonstration that lateral differences in the DTI-ALPS index vary according to brain ageing statuses. The two distinct profiles of the sleep-glymphatic function-cognition connections observed in relation to brain-PAD scores suggest that a preserved brain age may serve as a protective factor against age-related decline in glymphatic function. These findings may underscore the translational potential of brain age models as both clinical biomarkers and modifiable targets for interventions aimed at promoting healthy longevity and brain resilience.
Simultaneous digestive and metabolic disorders in pregnant dairy cows present significant diagnostic challenges, especially during the dry period when physiological adaptations obscure clinical signs. The concurrent occurrence of left displaced abomasum (LDA), liver abscessation, and traumatic reticuloperitonitis (TRP) is uncommon and highlights the diagnostic challenges associated with non-specific clinical signs during the dry period. A six-year-old Holstein cow, in her fourth lactation and at 276 days of gestation, presented with lethargy, diarrhea, and reduced feed intake. Clinical examination confirmed LDA, while blood biochemistry indicated hepatic dysfunction with elevated gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST) activities. A right-sided omentopexy was performed; however, the cow's condition deteriorated, requiring an emergency cesarean section. Despite intervention, the animal failed to improve and was euthanized. Postmortem examination revealed a large hepatic abscess (21 cm in diameter) containing approximately 5 L of purulent material, TRP caused by a 4-cm nail embedded in the reticulum, and acute abomasitis. The coexistence of these conditions suggests a possible association between traumatic, inflammatory, and metabolic processes; however, the exact sequence of disease development could not be definitively established. This case highlights the diagnostic complexity of concurrent metabolic and infectious disorders in late-gestation dairy cows. The findings emphasize the importance of early recognition, careful interpretation of clinical and laboratory findings, and comprehensive diagnostic evaluation in dry cows, where physiological adaptations and reduced monitoring intensity may delay detection of severe underlying disease.
Cancer pain affects 60%-80% of patients with advanced cancer, and approximately 30% of patients experience inadequate pain control. Although the World Health Organization (WHO) three-step analgesic ladder has substantially improved pain management, inadequate analgesia, opioid-related adverse effects, and refractory pain continue to pose significant clinical challenges. This narrative review critically evaluates recent advances in cancer pain management, including novel analgesics, optimized opioid formulations, nanomedicine, invasive interventions (intrathecal drug delivery, neuromodulation, and neurolysis), and complementary integrative therapies, aiming to provide up-to-date insights for clinicians and researchers. Novel analgesics targeting μ-opioid receptor bias, ion channels, and multitarget strategies have shown preclinical promise. Improved opioid formulations and nanomedicine-based approaches may enhance drug delivery and reduce toxicity. Fourth-step interventions, including intrathecal drug delivery, neuromodulation, and neurolysis, provide targeted options for selected patients with refractory cancer pain. Integrative therapies, including mind-body interventions, acupuncture, massage, music therapy, and game-based approaches, may improve symptom burden and quality of life, although evidence for direct analgesic effects remains limited. Cancer pain management is evolving toward a multimodal and increasingly personalized framework. Despite substantial progress, many emerging therapies lack robust cancer-specific validation. High-quality clinical trials, standardized treatment protocols, and improved translational strategies are needed to establish evidence-based precision cancer pain management.
Cancer metastasis contributes to the high mortality rate in patients and remains a significant challenge in treating solid malignancies. The limitations of current therapeutic interventions are underscored by the mere 5% survivorship of patients with metastatic disease. Since cancer stem cells (CSCs) are the major cause of metastatic spread, emerging therapeutic modalities specifically targeting CSCs present a lucrative approach to curtail metastatic disease. The literature demonstrating the promise of targeting CSCs to limit metastatic spread holds immense potential but remains scattered. This review provides concise knowledge of CSC targeting strategies and their impact on the metastatic burden in cancer patients. Current therapeutic strategies, early screening of cancer and reduction in smoking have drastically reduced the cancer-associated deaths by 34% in the US [1]. However, CSCs and therapy resistance pose major clinical challenges. Therefore, new way to address CSCs such as targeting stemness pathways, cellular plasticity and stress tolerance, nano theranostic approaches, the effect of phytochemicals and new radiotherapy technologies such as microbeam radiotherapy are being extensively studied. The detailed molecular studies on CSCs provide a platform for identifying factors intrinsic to cancer cells, host cells, and tumor microenvironment (TME) influencing stemness and overall metastasis. In addition to emerging anti-metastasis therapeutic modalities, the review provides information regarding exclusive targets and signalling molecules involved in metastasis. Simultaneous targeting of factors regulating CSCs and TME, along with standard of care therapies, proves a better strategy to tackle CSC heterogeneity and their adaptation for metastatic disease. Further approaches impacting CSCs offer a promising avenue for enhancing the effectiveness of cancer therapeutics and discovering new anti-metastatic drug candidates.
Robot-assisted distal pancreatectomy is increasingly recognized as an important minimally invasive option for lesions of the pancreatic body and tail. Given the technical complexity inherent to distal pancreatectomy, including deep operative planes, vascular dissection, splenic vessel management, and the persistent risk of postoperative pancreatic fistula, robotic systems may offer specific advantages in selected settings. However, although the number of relevant publications has continued to rise, the overall research landscape and thematic development of this field remain insufficiently and unsystematically characterized. The present study was designed to assess the global research status, knowledge structure, and evolving hotspots in the field of robot-assisted distal pancreatectomy through bibliometric and visualization analysis. A total of 254 eligible publications indexed in the Web of Science Core Collection between January 1, 2007 and December 31, 2025, including 210 articles and 44 reviews, were analyzed using Bibliometrix, VOSviewer, CiteSpace, and Scimago Graphica. The yearly publication output demonstrated a general increasing pattern, with more marked growth from the mid-2010s onward and the highest output recorded in 2025. Italy together with the United States remained the principal contributors across much of the study period, while China showed sustained growth in recent years. The United States ranked first in citation impact. Several institutions, including the University of Amsterdam, University of Verona, and University of Pisa, emerged as major contributors. Among the leading publication venues were Surgical Endoscopy and Other Interventional Techniques, Annals of Surgical Oncology, and Journal of Robotic Surgery. Citation and co-citation analyses showed that the intellectual structure of the field has been shaped mainly by studies focusing on surgical technique, perioperative outcomes, and comparisons with laparoscopic distal pancreatectomy. Keyword analysis indicated that spleen preservation, pancreatic fistula, laparoscopic comparison, learning curve, clinical outcomes, and multicenter evaluation are among the main research themes, with recent attention increasingly directed toward preservation strategies, outcome assessment, and more refined clinical application. In conclusion, research on robot-assisted distal pancreatectomy has expanded steadily and is moving from early feasibility-focused exploration toward a more specialized and clinically oriented stage. Future progress in this field will likely depend on stronger multicenter collaboration, more indication-specific evaluation, and more standardized evidence generation.
To determine Fraction of exhaled nitric oxide (FeNO) cut-off values that discriminate asthma exacerbation from control in Indian children with asthma and coexisting allergic rhinitis. Also, to evaluate the correlation between FeNO and Absolute eosinophil count (AEC). A prospective observational cohort study with repeated measurements was conducted at a tertiary-care hospital in western India (March 2023-December 2024). Children aged 4-12 y with both conditions were consecutively enrolled. FeNO and AEC were measured at baseline, 1 mo and 3 mo. Asthma and allergic rhinitis case definition followed Global Initiative for Asthma (GINA) 2023 and Allergic Rhinitis and its Impact on Asthma (ARIA) 2016 guidelines. Optimal cut-offs were derived by ROC analysis with the Youden index. Ninety-seven children (mean age 7.3 ± 2.2 y; 62.4% males) completed follow-up. FeNO and AEC correlated significantly during exacerbation (r = 0.361, p = 0.003) and control (r = 0.292, p = 0.036). A FeNO >20.5 ppb discriminated exacerbation with 77% sensitivity, 81% specificity, NPV 92.6%, PPV 52.6% (AUC 0.867, 95% CI 0.815-0.920; p <0.0001); the corresponding AEC was 505 cells/µL (AUC 0.828, 95% CI 0.769-0.887). For control, FeNO <14.5 ppb showed 55% sensitivity, 87% specificity, NPV 71% (AUC 0.739, 95% CI 0.675-0.803); corresponding AEC was 413 cells/µL. FeNO and AEC are useful, complementary biomarkers in Indian children with asthma and coexisting allergic rhinitis. The proposed thresholds (FeNO >20.5 ppb for exacerbation, <14.5 ppb for control) are substantially lower than American Thoracic Society (ATS)/ European Respiratory Society (ERS) recommendations, supporting population-specific paediatric reference values.
Although reproductive vaccines are essential in swine herd health programs, evidence on their safety across different physiological stages remains limited. This study evaluated the clinical and reproductive safety of Porcilis® EPL in sows and gilts under commercial field conditions. In a randomized, blinded, controlled trial, 200 females were allocated to treated or control groups within five physiological categories, of which 190 completed the study. Sows received a single dose and gilts a two-dose protocol. Clinical parameters (body condition, rectal temperature, general health, feed intake) and injection-site reactions were monitored for 14 days post-vaccination. Reproductive outcomes, including conception, litter size, stillbirths, mummification, and neonatal viability, were recorded. PCR testing for PCV2, PCV3, and PPV was performed on non-viable piglets. The vaccine was well tolerated, with no systemic adverse reactions and only mild, self-limiting injection-site swellings in some treated females. Body condition and temperature profiles remained within physiological limits. Reproductive performance did not differ between groups (p > 0.05). Pathogen detection frequencies were similar across treatments, indicating that vaccination did not measurably alter fetal susceptibility to endemic PCV2, PCV3, or PPV. Porcilis® EPL showed excellent clinical and reproductive safety when administered during different physiological stages in sows and gilts. The vaccine did not affect fertility, gestational outcomes, or perinatal survival and did not measurably alter pathogen detection under field conditions with natural pathogen exposure, supporting its safe integration into breeding herd vaccination programs. PCR detection of PCV2, PCV3, and PPV was included as an exploratory epidemiological assessment to distinguish vaccine-specific effects from endemic pathogen circulation. No differences were observed between groups, supporting that Porcilis® EPL did not influence susceptibility to non-target pathogens. This study provides a comprehensive, randomized, blinded field evaluation of the clinical and reproductive safety of Porcilis® EPL administered to sows and gilts at different physiological stages under real commercial conditions. By integrating detailed clinical monitoring, thermophysiological responses, body condition dynamics, reproductive performance, and molecular diagnostics of non-viable piglets, the study offers a multidimensional assessment of vaccine safety. The findings indicate that Porcilis® EPL is clinically well tolerated, does not compromise fertility or perinatal outcomes, and did not measurably alter pathogen detection under field conditions, including herds with endemic circulation of PCV2, PCV3, and PPV. This work helps address an important knowledge gap regarding the use of reproductive vaccines during sensitive gestational windows and supports evidence-based vaccination strategies for modern swine production systems.
BackgroundThe standard metric to assess the benefit of cancer screening is reduction in cancer-specific mortality. However, patients may benefit from downstaging of disease due to screening, even among those who would have survived late-stage disease absent screening.MethodsWe developed a model of stage and survival in the absence and presence of screening. Within each stage/survival category without screening, there are transition probabilities to various stage/survival and mode of detection (screen detected or not) categories under screening. The model includes rules for allowable transitions; for example, stage and survival are unchanged for non-screen detected cancers, and survival status changing from dying to surviving requires downstaging. A two-stage (early/late) model was fit to National Lung Screening Trial (NLST) data. The low-dose computed tomography (LDCT) arm was considered the screening arm and the chest radiograph arm the control (non-screening) arm.ResultsThere were 1032 and 993 lung cancer cases in the NLST LDCT and control arm, respectively. 15.2% of control arm cases were late-stage (III/IV) survivors. Their rate of transitioning to early-stage (I/II) survivors under screening was 18.4%, resulting in 2.8% (15.2% * 18.4%) of all cases transitioning from late-stage survivors under no screening to early-stage survivors with screening. 47.1% of late-stage control arm cases did not survive; their rate of transitioning to early-stage survivors under screening was 21.5%, resulting in 10.1% (47.1% * 21.5%) of all cases under no screening with that transition.ConclusionsModeling the effects of screening on stage and survival can help elucidate a more holistic set of screening benefits.
A luminescence resonance energy transfer (LRET)-regulated dual-readout lateral flow immunoassay (LFIA) is reported that integrates naked-eye colorimetric screening and near-infrared (NIR)-excited quantitative luminescence analysis on a single test strip. Core-shell upconversion nanoparticles (UCNPs) functionalized with E2-bovine serum albumin conjugates were immobilized on the test line as luminescent donors, while gold nanoparticle (AuNP)-labeled anti-E2 monoclonal antibodies served dually as colorimetric labels and efficient LRET acceptors. Time-resolved luminescence measurements confirmed an LRET efficiency of 18.8%, with the donor lifetime decreasing from 720 to 585 µs upon immunocomplex formation. Under optimized conditions, the assay was completed within 10 min. The luminescence mode exhibited a linear response over 1-500 ng/mL with a limit of detection of 1.37 ng/mL, while the visual mode enabled naked-eye discrimination at 20-40 ng/mL. This UCNP-AuNP LRET strategy provides a practical dual-readout format that balances operational simplicity and quantitative performance, offering a versatile platform for rapid on-site screening of small-molecule contaminants in complex matrices.