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This case report describes a patient with drug refractory paroxysmal atrial fibrillation (PAF). Rapid focal activations with multiple sharp spikes were continuously identified inside the left superior pulmonary vein (PV) during sustained AF. Among seven episodes of AF, cessation of rapid focal activations coincided with the conversion of AF to flutter (n = 4) or immediate AF termination (n = 3). Guided by sharp spikes in the PV, abrupt termination of AF occurred during radiofrequency energy application. Conclusively, rapid focal activations inside the PV are critical in AF maintenance. Cessation of these rapid focal activations underlies the mechanism by which AF converts to flutter. [ABSTRACT FROM AUTHOR]

Background/aims: Endoscopic radiofrequency ablation (ERFA) is a treatment option for superficial esophageal squamous cell neoplasia (ESCN), with a relatively low risk of stenosis; however, the long-term outcomes remain unclear. We aimed to compare the long-term outcomes of patients with widespread superficial ESCN who underwent endoscopic submucosal dissection (ESD) or ERFA., Methods: We retrospectively analyzed the clinical data of patients with superficial ESCN who underwent ESD or ERFA between January 2015 and December 2021. The primary outcome measure was recurrence-free survival., Results: Ninety-two and 33 patients with superficial ESCN underwent ESD and ERFA, respectively. The en bloc , R0, and curative resection rates for ESD were 100.0%, 90.2%, and 76.1%, respectively. At 12 months, the complete response rate was comparable between the two groups (94.6% vs 90.9%, p=0.748). During a median follow-up of 66 months, recurrence-free survival was significantly longer in the ESD group than in the ERFA group (p=0.004), while no significant differences in overall survival (p=0.845) and disease-specific survival (p=0.494) were observed. Preoperative diagnosis of intramucosal cancer (adjusted hazard ratio, 5.55; vs high-grade intraepithelial neoplasia) was an independent predictor of recurrence. Significantly fewer patients in the ERFA group experienced stenosis compare to ESD group (15.2% vs 38.0%, p=0.016)., Conclusions: The risk of recurrence was higher for ERFA than ESD for ESCN but overall survival was not affected. The risk of esophageal stenosis was significantly lower for patients who underwent ERFA.

Purpose: To examine the findings of pyomyositis by computed tomography (CT) imaging at autopsy to establish the correct diagnostic approach for this disease in the postmortem setting., Materials and Methods: A total of 6,964 autopsy cases with CT imaging from two forensic center databases were examined to identify primary pyomyositis. Basic demographics, external findings, postmortem CT findings, and autopsy results were reviewed., Results: Ten cases of primary pyomyositis were identified. All of the deceased individuals were older than 40 years of age without definitive evidence of human immunodeficiency virus infection. Five individuals had a history of trauma, with one case of trauma occurring more than 1 year previously. Pyomyositis was mostly located in the extremities. Three individuals showed pyomyositis in more than one muscle group. Only one individual showed signs of infection before the autopsy. Three individuals had grossly identifiable erythema. Nine individuals showed positive imaging findings, such as swelling, fat stranding, decreased density, fluid collection, and gas formation, on a CT scan. One individual had no findings of pyomyositis and this was discovered incidentally., Conclusion: This study shows differences from previous clinical case series of pyomyositis, such as the absence of young age groups and human immunodeficiency virus/acquired immunodeficiency syndrome cases, and a unique case of pyomyositis that occurred more than 1 year after a traumatic incident. Grossly identifiable erythema is rare, posing a considerable diagnostic challenge. However, CT imaging is useful in detecting infection., Competing Interests: Declarations. Ethical approval: All procedures performed in this research involving forensic autopsies were in accordance with the ethical standards of the institutional and/or national research committee and followed the guidelines applicable to postmortem research. Informed consent: As this study involved forensic autopsies, informed consent was not applicable. The use of autopsy data was approved by relevant legal and ethical authorities in accordance with institutional and national guidelines for postmortem research. Conflicts of interest: The authors declare that they have no conflict of interest., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aimed to evaluate the reliability and validity of the Binge Eating Disorder Screener-7 (BEDS-7) across 42 countries and 26 languages, assessing its reliability and validity as a screening tool for binge-eating disorder (BED) in diverse cultural contexts. Specifically, it sought to enhance early recognition of BED symptoms in primary care settings globally, contributing to a standardized framework for assessing BED., Method: The International Sex Survey, a cross-sectional online study, was conducted in 42 countries and 26 languages. A diverse community sample of 82,243 participants, aged 18 years or older, completed the BEDS-7 and measures of sexuality, mental health, substance use, and sociodemographic characteristics. Confirmatory factor analyses and tests of measurement invariance were employed to evaluate the reliability and validity of the BEDS-7 across languages, countries, genders, and sexual orientations., Results: The BEDS-7 demonstrated scalar factorial invariance across languages and countries, indicating consistent factor loadings and item intercepts. In contrast, the screener showed residual invariance across gender and sexual orientation groups, supporting its robustness across these demographics. Kruskal-Wallis tests revealed significant differences in BED symptoms across languages, countries, genders, and sexual orientations, with the highest BED scores observed among queer, pansexual, and gender-diverse individuals. The BEDS-7 also demonstrated adequate reliability (Cronbach's alpha > 0.80) and moderate criterion validity., Discussion: The findings provide further evidence of the reliability and validity of the BEDS-7 as a potential screening tool for identifying probable cases of BED globally, facilitating early intervention in primary care settings., (© 2025 The Author(s). International Journal of Eating Disorders published by Wiley Periodicals LLC.)

Ethnopharmacological Relevance: Tangshenning (TSN) is a traditional Chinese medicinal formula developed on principles of kidney tonification and collateral unblocking. TSN, formulated from Astragalus mongholicus Bunge, Rheum palmatum L., Ligusticum chuanxiong Hort., and Rosa laevigata Michx., has demonstrated significant clinical efficacy in the treatment of diabetic kidney disease (DKD). Our previous studies have suggested that TSN mitigates tubular injury in DKD by inhibiting ferroptosis, however, the precise molecular targets and mechanistic pathways underlying these effects remain to be fully elucidated., Aim of the Study: We investigated whether the Sestrin2/AMPK/PGC-1α axis serves as a key pathway mediating TSN's protective effects against tubular injury in DKD., Methods: In vivo, a spontaneous DKD mouse model was developed using KK-Ay mice. In vitro, human tubular epithelial cells (TECs) were used to establish high glucose and ferroptosis models, as well as a Sestrin2 knockdown model for further analysis. Molecular docking was utilized to examine the binding interactions between TSN's key active components and Sestrin2. Colocalization of Sestrin2 and GPX4 was assessed using dual fluorescence staining. Protein expression levels related to the Sestrin2/AMPK/PGC-1α pathway, ferroptosis markers (SLC7A11 and GPX4), and the tubular injury marker KIM-1 were quantified via Western blot analysis. In vivo, DHE staining, TUNEL staining, and ferrous ion content measurement were performed to evaluate ferroptosis levels in renal tissue. In vitro, the BODIPY 581/591 C11 probe and ferrous ion assay were used to assess ferroptosis levels in TECs. MitoSOX staining, JC-1 assay, and ATP level measurements were conducted to evaluate mitochondrial function in TECs., Results: In vivo, our results demonstrated that TSN improved renal function, alleviated tubular injury, and reduced pathological damage in DKD mice. Furthermore, TSN upregulated the protein expression of the Sestrin2/AMPK/PGC-1α axis and decreased ferroptosis-related markers in the DKD mouse model. Similarly, in vitro, TSN enhanced the expression of the Sestrin2/AMPK/PGC-1α pathway, restored mitochondrial function, and inhibited ferroptosis in TECs under high glucose and ferroptosis-inducing conditions. Additionally, downregulation of Sestrin2 impaired the therapeutic effects of TSN., Conclusion: TSN alleviates tubular injury in DKD by activating the Sestrin2/AMPK/PGC-1α pathway, restoring mitochondrial function, and inhibiting ferroptosis in TECs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background & Aims: A functional cure is an essential endpoint in the management of patients with chronic hepatitis B virus (HBV) infection. We evaluated the cumulative probability and predictors of functional cure in patients with chronic HBV infection after hepatitis B e antigen (HBeAg) seroconversion., Methods: We retrospectively analyzed 413 (249 males and 164 females) initially HBeAg-positive chronic HBV-infected patients who were followed up for a mean of 26.36 ± 0.53 years. All underwent HBeAg seroconversion during follow-up. A functional cure was defined as durable HBsAg and HBV DNA loss without antiviral treatment for more than 24 weeks., Results: After 10,888 person-years of follow-up, the cumulative probability of functional cure was 14.53% (n = 60). There were 24 (40%) subjects with functional cure after antiviral therapy. The annual functional cure rate was 0.55% per person-year, and increased to 0.96% per person-year after HBeAg seroconversion. In subjects with functional cure, the HBsAg and HBV DNA titers after HBeAg seroconversion were positively correlated with the time to functional cure (P < .001 and < .001, respectively). Multivariate Cox proportional hazards analysis of the cohort revealed that HBeAg seroconversion at <18 years of age, high-genetic-barrier nucleos(t)ide analogue(s) therapy before HBeAg seroconversion, and a serum HBsAg titer <1000 IU/mL at 18 months after HBeAg seroconversion were significant predictors of functional cure (P < .001, .001, and .001, respectively)., Conclusions: In a cohort of chronic HBV-infected patients with long-term follow-up, HBeAg seroconversion in childhood, high-genetic-barrier nucleos(t)ide analogue(s) therapy, and low HBsAg titers after HBeAg seroconversion were significant predictors of functional cure., (Copyright © 2025. Published by Elsevier Inc.)

Background: Public health issues related to tuberculosis still exist. Because Xpert MTB/RIF Ultra is more effective than conventional TB diagnostic techniques are, it is now regarded as an emerging technology. The diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculosis was assessed in this systematic study., Methods: We searched the PubMed, Cochrane, EMBASE, and Web of Science databases for pertinent literature published before January 18, 2024. The quality of the collected literature was assessed via Review Manager 5.3 software, which applies the quality assessment of diagnostic accuracy studies criteria. Using Metadisc 1.40 software, the sensitivity, specificity, and summary receiver operating characteristic curves were plotted and examined. Stata 12.0 was the program we utilized to assess publication bias in this investigation. The Prospero prospective register of systematic reviews included this study (reference number CRD42024569674)., Results: Analysis of 187 fourfold tables from 72 studies revealed that Xpert MTB/RIF Ultra demonstrated an overall pooled sensitivity of 76% and specificity of 95% for detecting pulmonary tuberculosis. The positive likelihood ratio (PLR) was 14.91, and the negative likelihood ratio (NLR) was 0.23, with an area under the curve (AUC) of 0.9351 and a diagnostic odds ratio (DOR) of 73.39. For detecting rifampin resistance, the combined sensitivity and specificity were 94% and 97%, respectively. The pooled PLR was 24.94, the NLR was 0.07, and the DOR was 429.05. The area under the summary receiver operating characteristic (SROC) curve was 0.9868., Conclusion: In conclusion, developing effective laboratory diagnostic tools for identifying Mycobacterium tuberculosis is essential for epidemiological research. This study demonstrated that Xpert MTB/RIF Ultra effectively diagnosed Mycobacterium tuberculosis infection, including pulmonary tuberculosis, as well as rifampin resistance, highlighting its potential as a valuable tool for both diagnosis and resistance detection., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Adults with Alzheimer's disease and Alzheimer's disease related dementias (ADRD) or frailty are susceptible to fractures. Opioid analgesics are frequently prescribed after fractures. Documenting post-fracture opioid discontinuation rates and predictors of discontinuation among adults with ADRD or frailty can inform clinical practice, identify potential disparities, and improve pain management guidelines. The objective of this paper was to investigate opioid discontinuation in opioid-naïve older adults who used opioids after an acute fracture., Methods: This retrospective cohort study included opioid-naïve Medicare fee-for-service beneficiaries (N = 33,027) ≥65 years of age who filled an opioid prescription within 30 days of a vertebral, lower extremity, or upper extremity fracture from 2013 to 2018. Beneficiaries were classified according to ADRD (yes/no) and frailty (yes/no) status using validated claims-based algorithms. The primary outcome was opioid discontinuation, defined as a 30-day supply gap. We estimated discontinuation rates with the Kaplan-Meier method and identified predictors of opioid discontinuation using Cox proportional hazards regression., Results: The 30-day opioid discontinuation rate was similar among non-frail beneficiaries without ADRD (81% [95% CI, 80%-81%]) and those who were non-frail with ADRD (83% [81%-84%]). Comparatively, 30-day discontinuation rates were lower among those with frailty and ADRD (76% [75%-77%]) and those with frailty alone (77% [75%-78%]). After adjusting for sociodemographic characteristics, health status, healthcare utilization, and calendar year, beneficiaries with both ADRD and frailty (HR, 0.90 [0.87-0.93]) and those with frailty alone (HR, 0.85 [0.82-0.89]), but not those with ADRD alone (HR, 1.06 [1.01-1.10]), were less likely to discontinue opioids compared with those without ADRD or frailty., Conclusions and Relevance: Our findings suggest that frailty, but not ADRD, was associated with a lower likelihood of opioid discontinuation among older adults who initiated opioids after an acute fracture. Further research is needed to understand how opioid deprescribing practices depend on patient and provider preferences., (© 2024 The American Geriatrics Society.)

The psychobiotic Limosilactobacillus fermentum PS150 (PS150), isolated from fermented meat sausage, has antidepressant, anxiolytic, and sleep-improving properties. This study investigated the safety of PS150 using a genome-based safety evaluation, antibiotic resistance profiles, mutagenicity, clastogenicity, 28-day subacute toxicity, and gastrointestinal tolerance. Bioinformatics analysis indicated that PS150 did not carry genes encoding antimicrobial resistance, virulence factors, or enzymes related to biogenic amine production. Additionally, PS150 was sensitive to the eight antibiotics tested. Ames test results showed no signs of increased reverse mutations following PS150 treatment. Further, PS150 treatment did not increase the frequency of chromosomal aberrations or number of micronuclei, and administration of PS150 (1.3 × 10 11  CFU/kg, 2.6 × 10 11  CFU/kg and 4.3 × 10 11  CFU/kg) for 28 days did not cause any toxicity or mortality in mice. PS150 exhibited superior gastrointestinal tolerance both in vitro and in vivo, enabling it to endure and survive the digestive processes. In conclusion, our results suggest that L. fermentum PS150 is safe in mice, supporting its potential as a psychobiotic candidate for human use. The 28-day "No Observed Adverse Effect Level (NOAEL)" is defined at the highest dose of 4.3 × 10 11  CFU/kg body weight/day for the PS150 powder under the test conditions employed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 1. Po-Lin Liao reports financial support was provided by National Science and Technology Council, Taiwan, ROC. Po-Lin Liao reports financial support was provided by Bened Biomedical Co., Ltd, Taiwan, ROC.2. Li-Hao Cheng, Chien-Chen Wu, Chin-Lin Huang, Yu-Hsuan Wei, Pei-Jun Wen reports a relationship with Bened Biomedical Co., Ltd., Taipei, Taiwan, R.O.C that includes: employment.3. The financial backers were not involved in designing the study, collecting data, or performing the analysis., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We compared adults with mitral stenosis (MS) to 8 controls (CONT) to see how pulmonary impedance and wave reflections differ at baseline and after balloon valvuloplasty., Methods: We separated the MS patients into groups according to mean pulmonary artery pressure: moderate (MOD; ≤ 26 mmHg, n = 21) and high (HIGH; > 26 mmHg, n = 33). We made baseline high-fidelity measurements in all patients, in the MS groups after vasodilation with nitroprusside, immediately and 4 months after balloon valvuloplasty., Results: Comparing MOD vs CONT, using the Kruskal-Wallis test with Bonferroni correction, reveals evidence for higher baseline input resistance (R) (489 vs 205 dyne-sec/cm 5 , P = 0.07); first harmonic of impedance modulus (Z 1 ) (97.3 vs 27.6 dyne-sec/cm 5 , P = 0.01); first zero crossing of impedance phase angle (F 0 ) (4.49° vs 2.19°, P = 0.02) but no difference in wave reflection index (P b /P f ). Baseline HIGH vs CONT comparisons reveal stronger evidence and larger differences than MOD for R (995 vs 205, P < 0.001); Z 1 (151 vs 27.6, P < 0.001); F 0 (5.25 vs 2.19, P < 0.001); as well as P b /P f (0.69 vs 0.42, P < 0.001). Responses to nitroprusside and valvuloplasty are also greater in the HIGH than MOD, but the HIGH parameters still differ from the CONT. Four months after valvuloplasty there is evidence for reverse remodeling in both groups. Further analyses reveal that sinus rhythm and younger age are potentially important factors for remodeling., Conclusion: MS causes alterations in pulmonary hemodynamics that differ according to pressure levels. These changes are only partially reversed immediately after valvuloplasty. There is evidence for reverse remodeling 4 months afterwards., Competing Interests: Declarations. Conflict of interest: No conflicts of interest, financial or otherwise, are declared by the authors. Ethical Approval: Each person (his/her parents if they were under age 21) gave informed consent for the investigative portion of the study. All studies in the controls and in patients with MS were performed in accordance with institutional guidelines for human research under separate protocols approved by the Institutional Review Board of the Veterans General Hospital, Taipei, Taiwan and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards., (© 2024. The Author(s).)

Background: Individuals with intellectual disabilities (ID) typically exhibit cognitive deficits. While single bouts of physical activity (PA) have shown cognitive benefits in typically developing individuals, the effects on those with ID are unclear. This study aimed to investigate the effectiveness of single bouts of PA on cognition in individuals with ID., Method: This registered review followed the PRISMA guidelines and searched for eligible studies on PubMed and Scopus., Results: Eight studies were included, showing that participants demonstrated transient improvements in cognition, including information processing speed, inhibition and working memory, following moderate aerobic-based intensity PA. However, findings regarding the optimal intensity or types of PA for enhancing specific cognitions, and the effects on higher-level cognition (e.g., planning), are limited., Conclusions: Single bouts of PA may transiently enhance cognition in adolescents and young adults with mild to moderate ID, but more rigorous research with a feasible protocol is required to refine exercise prescriptions for maximal cognitive benefits., (© 2025 John Wiley & Sons Ltd.)

This study aims to explore the mechanisms of the inhibitory effect of kaempferol on the invasion and metastasis of gastric cancer (GC) cells through network pharmacology prediction and experimental verification. It identifies core targets via PPI network analysis and finds that kaempferol binds to these targets well. In vitro experiments showed that kaempferol could inhibit the proliferation, colony formation, migration and invasion of GC cells. Western blotting indicated kaempferol may reduce AKT and GSK3β phosphorylation, leading to lower expression of invasion-related genes SRC, MMP9, CXCR4, KDR, and MMP2. Overall, kaempferol may prevent migration and invasion of GC cells via the AKT/GSK3β signaling pathway.

Our study aimed to investigate the neural mechanisms of taVNS in the motor symptoms of PD, focusing on the topological properties of cortical functional networks and cortical excitability. Thirty-two PD patients underwent functional near-infrared spectroscopy and transcranial magnetic stimulation evaluation prior to and after two-week taVNS, which were controlled by 20 healthy controls (HCs). PD patients exhibited decreased nodal efficiency (Ne) in the right M1 and increased Ne in the left pre-motor and supplementary motor area compared with HCs. The decreased Ne in the right M1 was negatively associated with UPDRS-III scores. Interestingly, taVNS treatment improved PD motor symptoms by increasing Ne in the right M1 and enhancing intracortical facilitation (ICF, ISI 10, and 15 ms). The increased Ne and ICF (ISI 15 ms) were negatively correlated with the decreased UPDRS-III scores. taVNS could improve nodal information processing efficiency in the M1 and enhance cortical facilitation to improve PD motor disorders., Competing Interests: Competing interests: The authors declare no competing interests. Consent for publication: Written informed consent for publication was obtained from all participants., (© 2025. The Author(s).)

Purpose: This study investigated whether Fibrosis-4 (FIB-4) score and its change can serve as predictors of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C (CHC) infection receiving direct-acting antivirals (DAAs)., Methods: This study identified 9679 patients who completed DAA treatment and achieved sustained virologic response (SVR) from the Taiwan Nationwide Real-World HCV Registry Program, and their risk of HCC was analyzed., Results: Multivariable Cox regression analyses identified diabetes mellitus (DM), alpha-fetoprotein (AFP) level, and FIB-4 score as independent predictors of HCC in both Model 1 (baseline) and Model 2 (SVR). Change in FIB-4 score (△FIB-4) of < -0.9086 from baseline to SVR achievement was a significant predictor of HCC only in Model 2 (SVR). In Model 2 (SVR), DM (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: 1.04-2.26, p = 0.033), FIB-4 score (≥3.25 vs. <3.25; HR: 2.40, 95% CI: 1.63-3.53, p < 0.001), △FIB-4 (greater reduction: <-0.9086 vs. smaller reduction: ≥-0.9086; HR: 1.85, 95% CI: 1.25-2.74, p = 0.002), and AFP level (≥20 vs. <20 ng/mL; HR: 16.40, 95% CI: 9.16-29.36, p < 0.001) were significant predictors of HCC. At 3 years, the cumulative HCC incidence was 10.67% in patients with an FIB-4 score of ≥3.25 upon achieving SVR and △FIB-4 of < -0.9086 and 1.72% in those with an FIB-4 score of <3.25 upon achieving SVR and △FIB-4 of ≥ -0.9086., Conclusions: Posttreatment FIB-4 score and its change from baseline can be used to stratify HCC risk in patients with CHC receiving DAAs., Competing Interests: Declaration of competing interest Dr. Cheng-Yuan Peng have served as an advisory committee member for AbbVie, Bristol-Myers Squibb, Gilead, and Roche. Dr. Ming-Lung Yu have received research support from Abbott, BMS, Gilead and Merck and served as a consultant of Abbvie, Abbott, Ascletis, BMS, Gilead, Merck and Roche and a speaker of Abbvie, Abbott, BMS, Gilead, Merck, and IPSEN. All other coauthors have no potential conflicts of interest., (Copyright © 2025 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Rationale and Objectives: Picture archiving and communication system (PACS) is integral to radiology, yet effective training to master PACS viewer tools remains challenging. This study aimed to evaluate the impact of a video-based curriculum on radiology residents' PACS confidence and technical proficiency., Materials and Methods: A prospective cohort study was conducted at a tertiary academic institution during 2022-2023, enrolling first-year (R1) and second-year (R2) radiology residents. The Intervention Group received a 30-minute instructional video on PACS tools 3 months after their orientation. The Reference Group did not receive additional training. Comfort levels and PACS task performance were assessed before and after the intervention., Results: A total of 24 residents participated, with 12 in each group. The Intervention Group showed a significant increase in self-reported confidence in PACS skills following the video intervention (median [interquartile range]=-1.01 [-1.30, -0.43] vs. 2.07 [1.37, 2.38], p<0.01). The Intervention Group maintained a higher confidence level at the R2 level compared to the Reference Group, though the difference was not statistically significant. Additionally, the Intervention Group completed their assigned PACS tasks in significantly less time (total time: 220.5 s [179.5, 259.5] vs. 315.0 s [211.8, 397.0], p=0.04)., Conclusion: The video-based PACS curriculum effectively improved radiology residents' technical skills and confidence. These results highlight the importance of supplementing on-the-job learning with formal technical training to reinforce proficiency with the PACS viewer., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cheng Ting Lin reports a relationship with Siemens Healthcare SAS that includes: funding grants. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objectives: The soluble guanylate cyclase (sGC) stimulator riociguat is approved for the treatment of pulmonary arterial hypertension and may have antifibrotic effects. However, in fibrotic tissues, oxidative stress and hypoxia can render sGC insensitive to sGC stimulators. sGC activators overcome this limitation. Here, we characterize the novel sGC activator, avenciguat, in preclinical models of SSc., Methods: Human microvascular endothelial cells-dermal (HMVEC-d) cultured in hypoxic conditions and activated human platelet-rich plasma were incubated with varying doses of avenciguat, and the levels of TGF-β2 and human CXC chemokine family ligand 4 (CXCL4) were measured, respectively. Treatment with avenciguat was analysed in mice with bleomycin-induced dermal and pulmonary fibrosis., Results: Avenciguat reduced hypoxia-induced synthesis of TGF-β2 by HMVEC-d and inhibited CXCL4 release by platelets. Moreover, avenciguat demonstrated antifibrotic effects on bleomycin-induced dermal and pulmonary fibrosis. RNA sequencing of affected skin uncovered a unique profile distinguishing avenciguat from riociguat. Avenciguat treatment resulted in deeper regulation of IFN-1 signalling and genes associated with immune response vs riociguat treatment., Conclusion: In preclinical studies, avenciguat shows the potential to influence vascular, fibrotic and immune-related processes in murine models of SSc. These studies suggest that it may offer therapeutic benefit across multiple aspects of SSc pathophysiology and support the rationale for further investigation in a Phase II clinical trial (VITALISScE™; NCT05559580) of avenciguat in SSc., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Uterine serous carcinoma and carcinosarcoma are aggressive forms of endometrial cancer with poor survival outcomes. Trastuzumab, a human epidermal growth factor receptor-2 (HER2)-directed monoclonal antibody, has demonstrated tumoricidal efficacy. However, clinical data regarding its efficacy in uterine serous carcinoma are limited, and there are no clinical data available for uterine carcinosarcoma. Therefore, this study aimed to ascertain the efficacy and safety of adding trastuzumab to carboplatin and paclitaxel as a frontline treatment for advanced-stage HER2-overexpressing uterine serous carcinoma and carcinosarcoma., Methods: This retrospective study used deidentified data from electronic health records from the TriNetX Research Network. Participants were identified using International Classification of Diseases codes, and HER2 positivity was confirmed through immunohistochemistry or fluorescence in situ hybridisation. Propensity score matching was employed to reduce confounders, and survival outcomes and adverse events were assessed., Results: Following propensity score matching, 280 patients with advanced HER2-positive uterine serous carcinoma or carcinosarcoma were analysed. The group of patients treated with carboplatin/paclitaxel + trastuzumab (CP + T) showed a significantly prolonged median overall survival compared to those treated exclusively with CP (41 months versus 25.2 months, hazard ratio [HR] = 0.51, p = 0.002) in both advanced-stage uterine carcinosarcoma and serous carcinoma. Specifically, patients with uterine carcinosarcoma experienced a prolonged survival benefit (HR = 0.39, p < 0.0001) when trastuzumab was added to their chemotherapy regimen, which surpassed the survival benefit observed in patients with uterine serous carcinoma (HR = 0.56, p = 0.04). However, patients who received trastuzumab experienced increased rates of hypertension, diarrhoea, and left ventricular systolic dysfunction., Conclusions: The addition of trastuzumab to frontline chemotherapy is effective in treating HER2-overexpressing uterine serous carcinoma and carcinosarcoma, particularly uterine carcinosarcoma. However, careful monitoring of adverse cardiac events is needed., Competing Interests: Declarations. Ethics approval and consent to participate: The TriNetX Research Network is fully compliant with the HIPAA and holds a waiver from the Western Institutional Review Board, given the deidentified and aggregate nature of the data. This manuscript presents original work and has not been previously published, nor is it under consideration for publication elsewhere. All authors have significantly contributed to the conception, design, analysis, or interpretation of the data presented in this manuscript. Consent for publication: The Consent for Publication of the Subjects in This Study Was Not Applicable, As the Data Collected Is Sourced from Electronic Health Records Obtained from the TriNetX Research Network in Cambridge, MA, USA. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by itching and redness, affecting individuals of all ages and significantly impairing their quality of life. The prevalence of AD is rising, posing serious health concern. Relief of itching is a primary treatment objective; however, steroid treatments can lead to adverse effects, including skin barrier thinning. Therefore, there is a pressing need for safer therapeutic alternatives. Limonene, a naturally occurring monocyclic monoterpene found in citrus peel oil, is widely utilized in food, cosmetics, and pharmaceuticals. Research has identified various biological activities of limonene, including antioxidative, anti-inflammatory, immunomodulatory, and antifibrotic properties. This study aims to investigate the therapeutic effects of limonene on atopic dermatitis, focusing on its anti-inflammatory potential., Methods: In this study, we investigated the expression levels of pro-inflammatory cytokines and chemokines, conducting histopathological analyses, and collecting physiological data from BALB/c mice with atopic-like dermatitis induced by 2,4-dinitrochlorobenzene (DNCB) and TNF-α/ IFN-γ-stimulated HaCaT cells., Results: In vitro studies indicated that limonene inhibited cytokine and chemokine expression in human keratinocytes and reduced phosphorylation in the MAPK, NF-κB, and JAK/STAT signaling pathways. In vivo, limonene mitigated DNCB-induced skin barrier damage and itching, improving physiological parameters such as trans-epidermal water loss, erythema, and ear thickness. Furthermore, it decreased the mRNA expression of pro-inflammatory cytokines., Conclusion: Limonene exhibits significant anti-inflammatory effects, highlighting its therapeutic potential for treating atopic dermatitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Sox30 has recently been demonstrated to be a key regulator of spermatogenesis. However, the precise roles of Sox30 in the testis remain largely unclear. Here, the specific functions of Sox30 in testicular cells were determined by single-cell sequencing and confirmed via pathological analyses. Sox30 loss appears to damage all testicular cells to different extents. Sox30 chiefly drives the differentiation of primary spermatocytes. Sox30 deficiency causes spermatocyte arrest at the early phase of meiosis I, with nearly no normally developing second spermatocytes and three new spermatocyte -subclusters emerging. In addition, Sox30 seems to play important roles in the mature phenotypes of Sertoli and Leydig cells, and the proliferation and differentiation of spermatogonia. The developmental trajectory of germ cells begins with spermatogonia and splits into two different spermatocyte branches, with Sox30-null spermatocytes and wild-type spermatocytes placed at divergent ends. An opposite developmental trajectory of spermatocyte subclusters is observed, followed by incomplete development of spermatid subclusters in Sox30-null mice. Sox30 deficiency clearly alters the intercellular cross-talk of major testicular cells and dysregulates the transcription factor networks primarily involved in cell proliferation and differentiation. Mechanistically, Sox30 appears to have similar terminal functions that are involved mainly in spermatogenic development and differentiation among major testicular cells, and Sox30 performs these similar crucial roles through preferential regulation of different signalling pathways. Our study describes the exact functions of Sox30 in testicular cell development and differentiation and highlights the primary roles of Sox30 in the early meiotic phase of germ cells., Competing Interests: Competing interests: The authors declare no competing interests Ethics approval: All animal studies were approved by the Animal Ethics Committee of the Chongqing Medical University and Army Medical University. Mouse experiments were carried out in accordance with the principles of Institutional Animal Care and Use Committee of Animal Experimentation of the Chongqing Medical University and Army Medical University. All methods were performed in accordance with the relevant guidelines and regulations., (© 2025. The Author(s).)

Introduction: Since TAVR was approved for lower-risk aortic stenosis (AS) patients, managing post-implantation conduction disturbances has become crucial, especially with self-expanding heart valves (SEV). This study aims to identify risk factors for conduction disturbances in such patients using a specific fluoroscopic cusp overlap (COL) technique., Methods: This retrospective study analyzed AS patients who underwent TAVR with SEV from 2019 to 2022, excluding those needing pacemakers or valve-in-valve procedures. Patients were grouped by conventional (CON) and COL techniques, with outcomes monitored using Valve Academic Research Consortium (VARC)-2 criteria., Results: In this cohort study of 114 patients, 17 were excluded due to pre-existing pacemakers. Forty-seven received SEVs using COL, and 50 with CON techniques. The COL group showed a significant reduction in new LBBB (27.7% vs. 46%, p  = 0.006) and PPI rates (4.3% vs. 18%, p  = 0.033) compared to the CON group. Deeper implantation depth below the non-coronary cusp (NCC) and left coronary cusp (LCC) was linked to an increased risk of conduction disturbances. Multivariate analysis identified smaller left ventricular outflow tract diameter, shorter membranous septum length, and greater pre-releasing implantation depth below the LCC as predictors of future PPI risk., Conclusion: The use of the COL technique significantly reduces the risk of newly developed conduction disturbances after SEV TAVR. Keeping SEV implantation depth within 1 mm of the membranous septum length and maintaining an implantation depth of <6 mm below the LCC before final release further minimizes the risk of PPI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor MS-L declared a past co-authorship with the author YT-L., (© 2025 Lee, Tsao, Lee, Lin, Liu, Hsiung, Yin and Wei.)

N 6 -methyladenosine (m 6 A) is a crucial mRNA epigenetic modification in eukaryotes, and its methylation regulation is associated with the proliferation and metastasis of diverse tumor cells. ALKBH5 functions as a demethylase for m 6 A and plays a role in the demethylation process, thus influencing tumor cell growth and migration. However, there are limited reports on selective small molecule inhibitors of ALKBH5. Herein, we designed and synthesized the ALKBH5 covalent inhibitor DDO-02267 by analyzing the protein structure of ALKBH5 and introducing salicylaldehyde warhead into noncovalent small molecule ligand. DDO-02267 specifically targeted Lys132 within ALKBH5, demonstrating significant selectivity for ALKBH5 in vitro. Additionally, DDO-02267 increased m 6 A levels and targeted the ALKBH5-AXL signaling axis in AML cells. The compound DDO-02267 can serve as a probe for investigating the biological function of mRNA demethylase and may inspire the development of future ALKBH5 inhibitors., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: The transition from medical school to residency, especially during the postgraduate year (PGY) internship, poses unique challenges as graduates navigate clinical practice complexities. Understanding PGYs' experiences is crucial for developing effective support strategies to promote their professional growth and well-being., Methods: This qualitative, longitudinal study followed ten PGYs from August 2021 to July 2023, using biannual audio diary based on open-ended questions to capture their experiences. Data analysis, guided by Activity Theory, focused on role conflicts and contradictions as PGYs transitioned from learners to practicing physicians., Results: The analysis revealed prevalent role conflicts and contradictions, primarily due to the tension between the PGYs' roles as learner and healthcare provider. Differences in objectives between PGYs and practicing doctors further exacerbated these conflicts, leading to clashes in priorities and care approaches. Consequently, PGYs experienced reality shock, lack of confidence, and feelings of incompetence, compounded by heavy workloads and exhaustion. These findings underscored the need for support and resources to help PGYs navigate these challenges and succeed in their healthcare roles., Discussions: Using Activity Theory to analyze the inherent challenges and contradictions within the PGY experience, this study offers insights for enhancing PGY preparedness, fostering both professional development and well-being. Drawing on recommendations supported by existing literature, which are stratified by tools, rules, and division of labor, we propose targeted strategies to address specific facets of the PGY role, thereby improving the overall training environment. This research highlights the need for tailored interventions to support PGYs through the challenging transition into clinical practice., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2025 The Author(s).)

Background and Aims: The Moral Incongruence Model of Pornography Use proposes that pornography-use-related problems may be present due to problematic pornography use (PPU) and/or moral disapproval (MD) of pornography use. Despite some supporting empirical evidence, no study has tested the presence of different pornography-use profiles based on individuals' behavioral dysregulation (i.e., PPU) and moral values concerning pornography use. The generalizability of previous findings to diverse populations has also been limited given the scarcity of studies conducted outside of Western countries., Methods: Using data from the International Sex Survey (42 countries, N = 66,994; Mage = 32.16 years, SD = 12.27), we conducted latent profile analysis to identify pornography-use profiles based on individuals' frequency of use, MD, and PPU. The profiles were compared along a wide range of pornography-use-related, sexuality-related, and psychological correlates., Results: Six pornography-use profiles were identified, including two increased risk groups (i.e., Increased risk of PPU without MD and Increased risk of PPU with some MD). Several factors differentiated between the increased risk vs. no/low risk profiles (e.g., relatedness satisfaction) as well as between the two increased risk profiles (e.g., religiosity). Apart from behavioral dysregulation, moral values concerning pornography use played an important role in distinguishing pornography-use profiles and demonstrated the importance of inquiring about MD when working with individuals with pornography-use-related problems., Conclusion: Findings also support recent calls for better-integrated sex therapy and sexual medicine perspectives into pornography-use-related problems research and care.

Background: The 72-h emergency department (ED) revisit rate is a key quality indicator. While some revisits stem from medical errors or inadequate initial treatment, others are due to disease progression or a lack of accessible care. The development of a risk assessment tool could identify high-risk patients and improve resource management., Methods: This study was conducted via an electronic health records system at a tertiary center in Taiwan. We derived a risk model via logistic regression and bootstrapping methods using a retrospective cohort of adults who underwent 72-h ED revisits between January 2019 and December 2020. The study population was divided into development (2019: 1224) and validation datasets (2020: 985). The primary outcome was high-risk return, defined as intensive care unit (ICU) admission or in-hospital mortality after 72-h ED return., Results: On the basis of the odds ratio, eight variables were independently associated with high-risk ED returns and subsequently included in the HANDLE-24 score (hypertension; symptoms of acute coronary syndrome; dysnatremia; dyspnea; liver disease; triage level escalation; and revisits within 24 h). The area under the receiver operating characteristic curve was 0.816 (95% CI: 0.760-0.871, p < 0.001) in the development dataset and 0.804 (0.750-0.858) in the validation dataset. Patients can be divided into three risk categories on the basis of the HANDLE-24 score: low [0-8.5], moderate [9-11.5] and high [12-22] risk groups. The ability of our risk score to predict the rates of hospital admission, ICU admission and in-hospital mortality was significant according to the Cochran‒Armitage trend test., Conclusion: The HANDLE-24 score represents a simple tool that allows early risk stratification and suggests more aggressive therapeutic strategies for patients experiencing ED revisits. The risk of adverse outcomes in ED adults after revisiting can be swiftly assessed via easily available information., Competing Interests: Declarations. Ethics approval and consent to participate: The authors affirm that our study adhered to the Declaration of Helsinki and we followed professional ethical guidelines when preparing this work. These guidelines include maintaining ethical treatment and respect for the rights of human participants and ensuring the privacy of participants and their data, such as ensuring that individual participants cannot be identified in reported results or from publicly available original or archival data. This study was approved by the Ethics Committee/Institutional Review Board of TVGH (Protocol Number: 2021–06-027CC), which waived the requirement for informed patient consent because of the retrospective nature of the analysis. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

DNA-PAINT enables nanoscale imaging with virtually unlimited multiplexing and molecular counting. Here, we address challenges, such as variable imaging performance and target accessibility, that can limit its broader applicability. Specifically, we enhance its capacity for robust single-protein imaging and molecular counting by optimizing the integration of TIRF microscopy with physical sectioning, in particular, Tokuyasu cryosectioning. Our method, tomographic & kinetically enhanced DNA-PAINT (tkPAINT), achieves 3 nm localization precision across diverse samples, enhanced imager binding, and improved cellular integrity. tkPAINT can facilitate molecular counting with DNA-PAINT inside the nucleus, as demonstrated through its quantification of the in situ abundance of RNA Polymerase II in both HeLa cells as well as mouse tissues. Anticipating that tkPAINT could become a versatile tool for the exploration of biomolecular organization and interactions across cells and tissues, we also demonstrate its capacity to support multiplexing, multimodal targeting of proteins and nucleic acids, and 3D imaging., Competing Interests: Competing interests Potential conflicts of interest for G.M.C. are listed on https://arep.med.harvard.edu/t/. C.-t.W. holds or has patent filings pertaining to imaging, and her laboratory has held a sponsored research agreement with Bruker Inc. C.-t.W. is a co-founder of Acuity Spatial Genomics and, through personal connections to G.M.C, has equity in companies associated with him, including 10x Genomics and Twist. A.P. holds a patent on ‘Genome Architecture Mapping’. P.Y. is also a co-founder, equity holder, director and consultant of Ultivue, Inc. and Digital Biology, Inc. All other authors declare no competing financial interest.

Background and Aims: Despite a growing body of research on pornography use among women, there is a lack of understanding of the problematic versus non-problematic nature. The current study aimed to investigate the relationship between women's motivations for pornography use and sexual wellbeing using a cross-sectional, self-report survey design among participants from 42 countries., Methods: The total sample included 82,243 participants, of whom 46,874 (57.0%) identified as women and were analyzed. The participants' age averaged at M = 29.67 years, with a standard deviation of SD = 10.11. Participants were asked to complete a questionnaire assessing their motivations for pornography use, as well as measures of sexual functioning, sexual desire, and sexual satisfaction., Results: Study results suggest that across cultures, women's motivations for pornography use are associated with their sexual wellbeing. Specifically, when women reported using pornography for their own pleasure or sexual curiosity, it was associated with fewer sexual functioning problems and higher sexual desire. Conversely, when women reported using pornography due to a lack of sexual satisfaction in their relationships, it was associated with more sexual functioning problems., Discussion and Conclusions: These findings highlight the need to consider the multifaceted nature of pornography use among women, including the usage motives, to fully understand associations with sexual wellbeing. Additionally, the study emphasizes the importance of conducting further research utilizing longitudinal designs, to establish the directionality between pornography use motivations and sexual wellbeing among women.

Background: Bone marrow (BM) is the dominant dose-limiting organ in [ 177 Lu]Lu-PSMA-617 therapy for patients with metastasized castration resistant prostate cancer, where BM dosimetry is challenging due to segmentation., Purpose: We aim to develop an automatic image-based segmentation method on peri-therapeutic sequential [ 177 Lu]Lu-PSMA-617 images for personalized BM dosimetry., Methods: Quantitative SPECT/CT imaging at 2, 20, 40 and 60 (n = 14)/200 (n = 16) h post [ 177 Lu]Lu-PSMA-617 injection were analyzed for 10 patients with 30 treatment cycles. X-means clustering was applied on the deep learning-based segmented lumbar spines CT images to classify the BM region. A single threshold method, two empirical segmentation methods (one sphere and five spheres), and gold standard manual segmentation were also implemented. The Dice similarity coefficient between BM masks of the X-means clustering and single threshold method was calculated as compared to the gold standard. BM mean absorbed dose (D mean ) was obtained for different segmentation methods. Absolute errors and Bland-Altman analysis were also evaluated for BM D mean derived from evaluated segmentation methods compared with the gold standard. Wilcoxon signed-rank test was performed for statistical evaluation. BM D mean was correlated with the change of platelets and white blood cells (WBC) pre- and post-treatment using Pearson correlation analysis., Results: In 30 cycles of 10 patients, the average Dice is 0.76 ± 0.18 for the X-means clustering method, as compared to 0.61 ± 0.19 for the single threshold method. The gold standard yields mean BM D mean of 0.46 ± 0.69 Gy. The X-means clustering method exhibits significantly (p < 0.01) lower mean absolute BM D mean (25.34 ± 64.48%) errors, followed by the single threshold (32.46 ± 69.49%), one sphere (50.53 ± 35.40%), and five spheres (72.73 ± 115.97%) methods. Bland-Altman analysis reveals that the X-means clustering method has a smaller D mean difference (0.0330 Gy) compared to the single threshold (0.0512 Gy), one sphere (-0.1903 Gy), and five spheres (0.2108 Gy) methods. Stronger correlations (r ≤ -0.65) are found between platelets/WBC changes and BM D mean from both the gold standard and X-means clustering methods than other methods., Conclusions: X-means clustering is feasible to segment the BM based on the CT images of peri-therapy SPECT/CT and shows advantages compared with the single threshold and empirical sphere segmentation methods., (© 2025 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

There is a persistent need for effective sensors to detect rare earth element ions (REEIs) due to their effects on human health and the environment. Thus, a simple and efficient fluorescence-based detection method for REEIs that offers convenience, flexibility, versatility, and efficiency is essential for ensuring environmental safety, food quality, and biomedical applications. In this study, 6-aza-2-thiothymine-gold nanoclusters (ATT-AuNCs) and bovine serum albumin/3-mercaptopropionic acid-AuNCs (BSA/MPA-AuNCs) were utilized to detect 14 REEIs (Sc 3+ , Gd 3+ , Lu 3+ , Y 3+ , Ce 3+ , Pr 3+ , Yb 3+ , Dy 3+ , Tm 3+ , Sm 3+ , Ho 3+ , Tb 3+ , La 3+ , and Eu 3+ ), resulting in the creation of a simple, sensitive, and multi-target fluorescence sensor array detection platform. We observed that REEIs exert various enhancement or quenching effects on ATT-AuNCs and BSA/MPA-AuNCs. Thus, these two probes function as double signal channels, with the different effects of REEIs serving as signal inputs. Pattern recognition methods, including hierarchical cluster analysis (HCA) and linear discriminant analysis (LDA), were used to assess the recognition performance of the constructed sensing system. Beyond the excellent ability to recognize individual REEIs, the platform is also capable of distinguishing mixed REEIs. Also, this approach was validated by applying it to detect REEIs in purified water samples. This method not only minimizes the need for synthesizing and optimizing new probes but also offers a novel approach for the determination and identification of diverse analytes, filling a gap in the detection of a large number of REEIs simultaneously.

EGFR is frequently overexpressed in non-small cell lung cancer, and EGFR plays a crucial role in the occurrence and progression of malignant tumors. Currently, drug resistance often develops following treatment with EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib. Therefore, It is essential to investigate new compounds that can effectively target EGFR overexpression. The polyphenols epigallocatechin-3-gallate (EGCG), found in tea, have demonstrated anti-cancer properties. In this study, we linked EGCG and erlotinib through a click reaction using polyglycol to form an EGCG-erlotinib conjugated compounds (EGCG-Erls). We then explored its biological activity through various experiments. The results indicated that the compound 10 exhibited a superior inhibitory effect on NCI-H1975 cells, reduced their cloning and migratory capabilities, promoted cell apoptosis, and inhibited cell cycle progression. Furthermore, it was observed that compound 10 can bind to the EGFR protein and effectively inhibit the expression of phosphorylated EGFR (p-EGFR) and its downstream signaling proteins. Overall, the study suggests that compound 10 may induce apoptosis and inhibit cell proliferation via the EGFR signaling pathway, providing a promising avenue for the development of new EGFR inhibitors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cheng-Ting Zi reports was provided by Yunnan Province Agricultural Bisic Research Joint Foundation and National Natural Science Foundation of China. Reports a relationship with that includes:. Has patent pending to. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: The aim of the study is to compare the mechanical stability of posterior malleolar fractures fixed with different screw types and locking plates in the management of trimalleolar ankle fractures using the finite element (FE) method., Methods: An FE model containing the distal tibia, fibula, talus, and calcaneus was created based on the computed tomographic images of a healthy man without any musculoskeletal disorders. The medial, lateral, and posterior malleoli were segmented using three virtual planes to create a trimalleolar fracture model, with the posterior malleolar fracture fragment comprising approximately 30% of the articular surface. Four different fixation approaches, including two partial thread cannulated screws (PTS), two full thread cannulated screws (FTS), and L-shaped (LLP) and T-shaped (TLP) locking plates with screws, were used to fix the posterior malleolar fracture. Two partial thread screws and a locking plate along with screws were used to fix the medial and lateral malleolar fractures, respectively. Two different loading conditions, namely static axial load and Achilles tendon force, were considered in the simulation., Results: Under axial load, the maximum gap opening distance of the posterior malleolar fracture with screws only was obviously larger than that with locking plates. The maximum gap distance was 0.12 mm, 0.08 mm, 0.04 mm, and 0.05 mm in the PTS, FTS, LLP, and TLP, respectively. Under Achilles tendon force, the maximum gap opening distance were 0.12, 0.1, 0.03, and 0.1 mm, in the PTS, FTS, LLP, and TLP, respectively, under Achilles tendon force., Conclusion: The results suggest that locking plates offer greater stability and reduce the fracture gap opening for posterior malleolar fractures involving 30% of the distal tibial articular surface in the fixation of trimalleolar ankle fractures., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in compliance with the principles of the 1964 Declaration of Helsinki and its later amendments. This study was approved by the Institutional Review Board of National Cheng Kung University Hospital (No: A-ER-109-451). Informed consent was obtained from the subject before the CT imaging. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: The role of syngameons in adaption to microgeographical environmental heterogeneity is important and could be one of the sources of rich species diversity in tropical forests. In addition, negative frequency- or density-dependent selection is one of the major processes contributing to the maintenance of genetic diversity., Methods: To assess genetic factors that affect the fitness of seedlings of Rubroshorea curtisii , a dominant canopy tree species in hill dipterocarp forests, the inter- and intra-population genetic structure of individuals from natural populations and individuals at two permanent plots in a hill dipterocarp forest with reproductive stage was studied. Further, a total of 460 seedlings derived from six mother trees in the plot were raised in a nursery, and their pollen donors were identified using genetic marker based paternity assignment. Seed weight, bi-parental genetic relatedness, and bi-parental genetic heterogeneity based on the clustering analysis were used to analyze their effects on seedling fitness., Results: A Bayesian based clustering analysis revealed that three genetically distinct clusters were observed in almost all populations throughout the distributional range of the species in Malay Peninsula and provided the optimum explanation for the genetic structure of 182 mature individuals in the plots. The two clusters showed larger genetic differentiation from the ancestral admixture population, but the other one was not differentiated. The bi-parental larger genetic heterogeneity was associated with a significantly higher probability of seedling survivorship, and likewise, higher performance of vertical growth of the seedlings; but the seed weight and genetic relatedness did not significantly affect those., Discussion: This evidence suggests that fitter seedlings derived from mating between parents with different genetic clusters contribute to maintaining genetic diversity through negative frequency-dependent selection and may have an important role in adaptation in the tropical forest plant community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Tani, Ng, Lee, Lee, Muhammad, Kondo, Tsumura, Sugiyama, Niiyama, Ripin, Kassim and Musa.)

Enthalpy is often the focal point when designing monomers for polymer circularity, but much less is explored on how entropy can be exploited to create polymers with synergistic circularity and properties. Here, we design a series of spiro-lactones (SLs) with closed-chain cycloalk(en)yl substituents at the α,α-position of δ-valerolactone (δVL), which, when combined with the parent δVL and gem -α,α-dialkyl-substituted δVL with open-chain alkyl groups, provide a desired platform for exploring the circular polymer design by focusing on the entropy change of polymerization. These SLs exhibit finely balanced (de)polymerizability that is regulated chiefly by entropy differentiation, allowing both the facile synthesis of polyester PSLs ( M n up to 1000 kg mol -1 ) in a living fashion and selective depolymerization of the PSLs to completely recover monomers under mild conditions (using a recyclable catalyst at 100 °C). One such PSL is semicrystalline ( T m = 134 °C), strong (ultimate strength = 43 MPa), hard (modulus = 1.85 GPa), and modestly flexible. These notable mechanical properties are bolstered by its superior barriers to oxygen and moisture permeation compared to common packaging materials. In addition, this PSL can be postfunctionalized to a recyclable OH-containing PSL that shows higher adhesion strength than the comparative commercial adhesives.

Background: Type 1 Diabetes (T1D) is a growing global health concern, with a notable rise in incidence in Saudi Arabia. Despite the potential benefits of early detection through screening programs, such initiatives are currently lacking in Saudi Arabia and other Arab countries., Objective: To evaluate the feasibility, acceptability, and cost-effectiveness of a T1D screening program targeting high-risk individuals, specifically children with a first-degree relative diagnosed with T1D., Methods: The VISION-T1D program is a prospective cohort study focused on the early detection of pre-symptomatic T1D by screening children aged 2-18 years. The primary screening method involves testing for islet autoantibodies, including insulin autoantibodies (IAA), glutamic acid decarboxylase autoantibodies (GADA), IA-2 autoantibodies (IA-2A), and Zn-transporter 8 (ZnT8) autoantibodies. Optional genetic testing, including HLA phenotyping and the Genetic Risk Score (GRS), is offered. Outcomes include the feasibility of the screening process, prevalence of early-stage T1D, psychological impacts, educational interventions effectiveness, progression rates to Stage 3 T1D, and the economic viability., Results: The VISION-T1D program began in May 2024. As of December 2024, 176 families have been enrolled. Data collection will continue until April 2025, with final data analysis projected for mid-2025., Conclusions: The VISION-T1D study provides a practical approach to T1D screening tailored to the healthcare landscape of Saudi Arabia. The insights gained from this pilot program will inform the development of a national, population-based screening initiative designed to reduce diabetic ketoacidosis (DKA) at diagnosis, improve long-term outcomes, and alleviate the economic burden of T1D. The VISION-T1D initiative could also serve as a scalable and sustainable model that can be adopted internationally, contributing to global efforts to manage and prevent T1D., Clinicaltrial: ClinicalTrials.gov NCT06513247.

Long interspersed element-1 (LINE-1, L1) retrotransposons are the most abundant protein-coding transposable elements (TE) in mammalian genomes, and have shaped genome content over 170 million years of evolution. LINE-1 is self-propagating and mobilizes other sequences, including Alu elements. Occasionally, LINE-1 forms chimeric insertions with non-coding RNAs and mRNAs. U6 spliceosomal small nuclear RNA/LINE-1 chimeras are best known, though there are no comprehensive catalogs of LINE-1 chimeras. To address this, we developed TiMEstamp, a computational pipeline that leverages multiple sequence alignments (MSA) to estimate the age of LINE-1 insertions and identify candidate chimeric insertions where an adjacent sequence arrives contemporaneously. Candidates were refined by detecting hallmark features of L1 retrotransposition, such as target site duplication (TSD). Applying this pipeline to the human genome, we recovered all known species of LINE-1 chimeras and discovered new chimeric insertions involving small RNAs, Alu elements, and mRNA fragments. Some insertions are compatible with known mechanisms, such as RNA ligation. Other structures nominate novel mechanisms, such as trans-splicing. We also see evidence that LINE-1 loci with defunct promoters can acquire regulatory elements from nearby genes to restore retrotransposition activity. These discoveries highlight the recombinatory potential of LINE-1 RNA with implications for genome evolution and TE domestication.

Background & Aims: Body composition is an objective assessment reflecting nutritional status and is highly gender different. Surgical resection, the standard treatment for early-stage hepatocellular carcinoma (HCC), is an energy-consuming major operation that would affect body composition. However, the impacts of body composition on the post-operative prognosis of HCC are still uncertain. In this study, we aimed to investigate surgery-related changes in body composition and the impacts on clinical outcomes of HCC after surgical resection distinguished by gender., Method: From January 2013 to December 2018, 401 consecutive patients who received surgical resection for HCC in Taipei Veterans General Hospital were retrospectively reviewed. Cross areas of adipose and muscle mass were measured at L3 vertebral level from peri-operative computed tomography by Slice-O-matic software; body composition indices were thus calculated. Factors associated with survivals were analysed., Results: Body composition indices did not change significantly after surgical resection of HCC in both males and females. Higher pre-operative intramuscular adipose tissue index (IMATI) (hazard ratio [HR]: 2.059, p = 0.002) and lower ratio of subcutaneous to visceral adipose tissue index (SATI/VATI) (HR: 1.681, p = 0.028) were independent predictors of worse overall survival (OS) in male patients. In females, higher pre-operative IMATI (HR: 3.053, p = 0.001) was the only body composition-related factor predicting OS., Conclusion: Surgical resection contributed minor changes in body composition in patients with early HCC. Myosteatosis and subcutaneous to visceral fat ratio were survival predictors in male patients, but myosteatosis was the only body composition-predictor of survival in females., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Klebsiella pneumoniae is a Gram-negative bacterium that can cause infections, especially in individuals with diabetes. Recently, more hypervirulent strains have emerged, posing a threat even to healthy individuals. Understanding how K. pneumoniae regulates its virulence factors is crucial. Acetyl-phosphate (AcP) is essential for bacterial metabolism and can affect virulence factor expression. However, the role of the Pta-AckA pathway, which regulates AcP levels, in K. pneumoniae pathogenesis remains unclear., Methods: Deletion mutants lacking the pta and ackA, involved in AcP production and hydrolysis, were generated in K. pneumoniae CG43S3. Their effects on AcP levels, the patterns of global acetylated protein, capsular polysaccharide (CPS) amount, serum resistance, type 3 fimbriae expression, biofilm formation, and virulence in G. mellonella larva were assessed., Results: Deletion of ackA in K. pneumoniae CG43S3 led to AcP accumulation, while pta deletion abolished AcP synthesis when grown in TB7+1 % glucose. This pathway influenced global protein acetylation, with pta deletion decreasing acetylation and ackA deletion increasing it. Additionally, pta deletion decreased the CPS amount, serum resistance, and type 3 fimbriae expression, while ackA deletion increased these factors. Furthermore, deleting pta and ackA attenuated the infected larva's virulence and death rate., Conclusion: Our findings highlight the critical role of the Pta-AckA pathway in K. pneumoniae pathogenesis. This pathway regulates AcP levels, global protein acetylation, CPS production, serum resistance, and type 3 fimbriae expression, ultimately impacting virulence. The information provides insights into potential therapeutic targets for combating K. pneumoniae infection., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Mild autonomous cortisol secretion (MACS) is common in adrenal adenomas, including patients with primary aldosteronism (PA) with aldosterone-producing adenomas (APA). This study investigated the impact of MACS on cardiac remodeling and diastolic dysfunction in patients with APA., Methods: We prospectively enrolled 483 patients with APA. MACS was defined as a cortisol level >1.8 μg/dL after an overnight dexamethasone-suppression test (DST). Clinical, biochemical, and echocardiographic data were collected at baseline and one-year following targeted treatments., Results: In this prospective cohort, 21% of patients with APA had concurrent MACS. Patients with MACS were older, had a higher prevalence of diabetes, larger adrenal tumor size, higher left ventricular mass index (LVMI), and worse diastolic function (E/e'). Multivariable linear regression analysis showed that concurrent MACS with APA was an independent risk factor for higher LVMI and worse E/e'. Among patients who underwent adrenalectomy, both those with and without MACS showed significant improvements in LVMI and E/e'. In contrast, among patients who received mineralocorticoid receptor antagonist (MRA) treatment, significant LVMI improvement was only observed in patients without MACS. MRA therapy did not improve E/e' regardless of the presence or absence of MACS., Conclusions: The presence of MACS in patients with PA was associated with worse cardiac hypertrophy and diastolic dysfunction. Surgical adrenalectomy was able to effectively reverse cardiac remodeling in patients with PA and concurrent MACS; however, MRA therapy was not associated with significant improvements in cardiac function. These findings highlight the independent deleterious effects of cortisol on cardiovascular disease in PA., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2025. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

An 8-week regimen of glecaprevir/pibrentasvir is recommended for treatment-naïve patients with chronic hepatitis C (CHC). In alignment with the Taiwanese government's objective to eliminate hepatitis C by 2025, this study aimed to provide real-world evidence on the use of this regimen in treatment-naïve patients with chronic kidney disease (CKD) by using data from the Taiwan Association for the Study of the Liver HCV Registry (TACR). CKD was defined by an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m 2 or higher with proteinuria persisting for over 3 months. Patients were categorized as having early CKD (eGFR ≥45 mL/min/1.73 m 2 ) or pre-end-stage renal disease (pre-ESRD) (eGFR <45 mL/min/1.73 m 2 ). Among 1072 patients who received at least one dose of the regimen, 1054 had available data for assessing sustained virologic response at 12 weeks posttreatment (SVR12). The overall SVR12 rate was 99.6%, with rates of 99.7% for pre-ESRD patients and 99.6% for early CKD patients. Subgroup analysis showed 100% efficacy for genotype 3 and dyslipidemia, 99.5% for diabetes, 99.4% for cardiovascular disease, 96.9% for a history of cerebral vascular accident, and 95.5% for patients with a history of drug injection or HIV co-infection. Adverse events were reported in 16.8% of patients, with 0.8% experiencing serious events, and only two cases were treatment-related. Renal function significantly improved, with overall eGFR increasing from 39.2 to 41.9 mL/min/1.73 m 2 . Early CKD patients showed an eGFR rise from 53.5 to 57.1, while pre-ESRD patients improved from 27.1 to 29.2 at SVR12. The study concluded that the 8-week regimen is highly effective, well-tolerated, and associated with significant renal function improvement in treatment-naïve CHC patients with both early CKD and pre-ESRD., (© 2025 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: Adverse childhood events (ACEs) have been associated with an increased risk of psychiatric disorders in young adulthood. To identify at-risk individuals and potential strategies to combat the negative impacts of ACE, this study investigated the mediating role of exercise in the relationship between psychological distress and ACEs. Further, we examined the moderating effect of the BDNF polymorphism in the mediation relationship., Methods: Participants (N = 750, Mage = 20.1 years) completed questionnaires assessing ACEs divided into adverse environment (AE) and childhood maltreatment (CM), exercise, and psychological distress. Salivary genomic DNA was used for genotyping. The significance of the moderated mediation model was assessed using bootstrapping., Results: There was a significant association between ACEs and psychological distress mediated by exercise. After addition of BDNF polymorphism, we found that the effect of ACEs on psychological distress through exercise was moderated by the BDNF polymorphism (index of moderated mediation = -0.19, [-0.48, -0.04], p-value ≤0.05). Further dividing ACE into AE and CM, the moderated mediation relationship remains significant only with AE (index of moderated mediation = -0.41, [-0.99, -0.10], p-value ≤0.05)., Conclusions: The interaction between BDNF polymorphism and exercise may be a suitable target for interventions in ACEs-experienced individuals for the prevention or reduction of psychological distress., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

The nanoscale control of phase transition in correlated materials offers significant insight into phase transition dynamics for the advancement of future nanoelectronics devices. This study explores the phase transition phenomenon in vanadium dioxide (VO 2 ), focusing on the heterogeneous phases evolved after low-pressure plasma irradiation on VO 2 thin films, a strong electron-correlated material. The modulation in the Argon (Ar) plasma power reveals the formation of homogeneous and heterogeneous phases with variable resistive states at room temperature. High-resolution transmission electron microscopy (HRTEM) is observed with the change in interplanar spacing revealing monoclinic (M1) at 0W, monoclinic-tetragonal rutile (phase coexistence, M1-R) at 50W, and tetragonal rutile (R) at 90W. Dielectric force microscopy (DFM) shows distinct dielectric responses corresponding to different phases, characterized by potential differences of 3 mV (M1), 5 mV (M1-R), and 7.44 mV (R) phases. The coexistence of M1-R phase is stabilized and examined at room temperature, with variations in the charge carrier density observed relative to M1 and R phases individually. The phase change in VO 2 is found to be reversible, enabling stable resistive states even after the plasma is removed. The changes in plasma geometry help find and stabilize unstable phases, which can be useful in nanoelectronics., (© 2024 Wiley‐VCH GmbH.)

Background: Differences of treatment outcome between full or reduced dose of tissue plasminogen activator (tPA) for bridge mechanical thrombectomy (MT) in the extended time window have not been clearly established. We aimed to present real-world results of bridge MT with different tPA dosages in the standard and extended windows., Materials and Methods: Patients with anterior circulation stroke treated with MT between 2017 and 2021 at two stroke referral centers were retrospectively reviewed. Bridge MT with tPA were categorized as full (0.9 mg/kg) or reduced (<0.9 mg/kg) dose. Standard window (SW) cohort was defined as MT performed within 6 h of acute ischemic stroke onset, while those beyond 6 h as the extended window (EW) cohort. 90 days Modified Rankin Scale (mRS) score, technical treatment success, in-hospital mortality, and post-treatment hemorrhage were analyzed., Results: A total of 423 patients met the inclusion criteria, 218 of which treated in the SW, while 205 treated in the EW. Within the SW cohort, the full-dose tPA group demonstrated a higher proportion of good functional outcome (GFO) at 90 days (mRS0-3) versus reduced (49% vs 21%, p = 0.0358). The overall GFO of SW was higher than that of the EW cohort (33% vs 20%, p = 0.0480). Within the EW cohort, GFO was similar between full and reduced dose groups. Successful reperfusion rate was lower in SW versus EW cohorts (39% vs 58%, p = 0.0199)., Conclusion: In real-world practice, the GFO of bridge MT is better than MT alone. The tPA dosage is not a determining factor of GFO in EW MT., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is responsible for a significant number of cancer-related deaths worldwide. Targeted drugs have been used for anti-liver cancer treatment in the advanced stage, while their efficacy is greatly compromised by development of drug resistance. Drug resistance is a complicated process regulated by intrinsic and extrinsic signals and has been associated with poorer prognosis in cancer patients. In the current study, online available dataset analysis uncovered that angiopoietin-like protein 3 (ANGPTL3) manifested lower expression in sorafenib-resistant liver cancer cell lines. Additionally, ANGPTL3 was downregulated in HCC tissues, with its expression positively correlated with good prognosis. Functionally, ectopic expression of ANGPTL3 re-sensitized sorafenib-resistant cells, enhancing the sorafenib-induced reduction in cell viability and migration by suppressing zinc finger protein SNAI1 (SNAI1) expression and the protein stability of carnitine O-palmitoyltransferase 1, liver isoform (CPT1A). Clinical correlation analysis revealed that ANGPTL3 was negatively associated with SNAI1 expression. In conclusion, we identify a novel association between ANGPTL3, SNAI1 and CPT1A on sorafenib therapeutic response. Targeting ANGPTL3/SNAI1/CPT1A axis may serve as a therapeutic approach to improve prognosis of liver cancer patients with sorafenib resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)