Objective: To quantitatively analyze and compare the forces and moments generated by thermoformed polyethylene terephthalate glycol (PETG) and direct-printed TC-85 clear aligners (CAs), with various margin designs, during premolar rotation. Methods: In total, 132 CAs were fabricated and divided into four groups (n = 33 per group). Group C consisted of thermoformed PETG aligners with a 2 mm gingival margin. Group E comprised direct-printed TC-85 aligners with equi-gingival margin, whereas Group G utilized direct-printed TC-85 aligners with 2 mm gingival margins.Finally, Group T featured direct-printed TC-85 aligners with an additional 1 mm thickness at the mesial embrasure. The forces and moments were measured using a 6-axis force/moment transducer at 2°, 3°, and 4° of rotation. All measurements were conducted at 37°C to simulate intraoral conditions. Forces were measured in the buccolingual, anteroposterior, and vertical directions, while moments were measured in the mesiodistal, buccolingual, and rotational planes. Results: The PETG aligners (Group C) showed significantly increased buccal and posterior force across the rotation angles (P < 0.05), whereas the intrusive force remained consistent. In contrast, the TC-85 aligners maintained consistent forces across all rotation angles.Direct-printed aligners demonstrated significantly lower intrusive forces than PETG aligners (P < 0.001). Group T exhibited reduced unwanted forces while maintaining effective rotational moments. Furthermore, all direct-printed aligners showed more predictable force delivery patterns than thermoformed aligners. Conclusions Direct-printed TC-85 aligners demonstrated superior force consistency and reduced unwanted side effects compared with traditional PETG aligners. Although marginal design modifications did not significantly improve rotational efficiency, they effectively reduced unwanted intrusive forces.

Donepezil, an acetylcholinesterase inhibitor, is widely used for managing the symptoms of Alzheimer’s disease (AD), yet its clinical response varies widely among individuals. This study aims to investigate the influence of CYP2D6 genetic variants on donepezil concentration, treatment response, and adverse effects in Korean patients with AD dementia. We conducted a longitudinal study involving 76 patients receiving either 5 mg or 10 mg of donepezil. Genetic testing identified 9 CYP2D6 alleles, categorizing patients by metabolizing abilities. Blood sampling for plasma concentrations of donepezil were performed at steady-state. Mini-Mental State Examination (MMSE) were conducted at 12, 24 and 36 months after the initiation of treatment. Adverse events were collected throughout the study period.Donepezil plasma concentrations differed significantly among metabolizer statuses (mean 56.8 ± 27.1 ng/ml in normal metabolizers vs. 69.6 ± 30.1 ng/ml in intermediate metabolizers, p = 0.042), but these differences did not affect cognitive function over three years as assessed by MMSE. Additionally, there was no significant correlation between donepezil plasma concentration and adverse events. Our study is the first to elucidate the associations between CYP2D6 genotype and the concentration, clinical response or adverse events of donepezil in Korean patients with AD dementia. Larger studies are necessary to fully understand the impact of CYP2D6 genetic variants on therapeutic outcomes with donepezil.

and Relevance: Severe necrosis and mild fibrosis were observed in the liver and forelimb skeletal muscles. Based on histological analysis, we diagnosed iron overload myopathy by secondary hemochromatosis. Secondary hemochromatosis with severe muscle atrophy and myositis is very rare, and this is the first report of iron-overload myopathy in a dog.

Background and Objectives: The risk profiles, procedural characteristics, and clinical outcomes for women undergoing bifurcation percutaneous coronary intervention (PCI) are not well defined compared to those in men. Methods: COronary BIfurcation Stenting III (COBIS III) is a multicenter, real-world registry of 2,648 patients with bifurcation lesions treated with second-generation drug-eluting stents.We compared the angiographic and procedural characteristics and clinical outcomes based on sex. The primary outcome was 5-year target lesion failure (TLF), a composite of cardiac death, myocardial infarction, and target lesion revascularization. Results: Women (n=635, 24%) were older, had hypertension and diabetes more often, and had smaller main vessel and side branch reference diameters than men. The pre- and post-PCI angiographic percentage diameter stenoses of the main vessel and side branch were comparable between women and men. There were no differences in procedural characteristics between the sexes. Women and men had a similar risk of TLF (6.3% vs. 7.1%, p=0.63) as well as its individual components and sex was not an independent predictor of TLF. This finding was consistent in the left main and 2 stenting subgroups. Conclusions In patients undergoing bifurcation PCI, sex was not an independent predictor of adverse outcome.

Background: Although total intravenous anesthesia (TIVA) with propofol and remifentanil is frequently used to optimize intraoperative neurophysiological monitoring (IONM), the exact effect of remimazolam on IONM remains unknown. Here, we compared the effects of propofol and remimazolam along with remifentanil on IONM during TIVA. Methods: In this prospective, double-blind, randomized controlled trial, 64 patients requiring IONM during cervical spine surgery were administered either propofol (Group P) or remimazolam (Group R). The preoperative latencies of the somatosensory-evoked potentials (SEP; N20 for the median nerve and P37 for the tibial nerve) were measured. SEP latencies and amplitudes and motor-evoked potential (MEP) amplitudes were measured 30 min after anesthetic induction (T1), 30 min after surgical incision (T2), after laminectomy or discectomy (T3), immediately after plate insertion or pedicle screw fixation (T4), and before surgical wound closure (T5). The primary outcome was the between-group difference in the N20 latency changes measured at T1 and preoperatively. Results: The change in SEP latencies including N20 and P37 at T1 compared with preoperative time was not significantly different between Groups P and R. Except for the amplitude of the right abductor brevis, there was no significant group-by-time interaction effect for intraoperative MEP amplitudes or SEP latencies and amplitudes. Conclusions TIVA with remimazolam and remifentanil for cervical spine surgery yielded stable IONM, comparable to those observed with conventional TIVA with propofol and remifentanil. Further clinical trials are needed in other surgical contexts and with more diverse patient populations to determine the effects of remimazolam on IONM.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by highrecurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ri-bose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations.This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potentlyinhibited CHK2 (IC50 : 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancingDNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy—resistance in BRCA-proficient cancers.In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.

Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS. Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches. Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability, and homologous recombination deficiency scores, which were essential for clinical decision-making. Conclusion TE-WGS is a comprehensive approach in personalized oncology, matching TSO500’s key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Background/Aims: Chronic gastroesophageal reflux disease (GERD) requires symptom relief and treatment of associated conditions. In this study, we aimed to compare anti-reflux mucosectomy (ARMS) and Stretta radiofrequency (SRF) for treating patients with chronic GERD who are unresponsive to proton pump inhibitors (PPIs) and to identify the indications for each procedure. Methods: Data of patients who underwent ARMS or SRF between March 2021 and April 2023 were analyzed. Changes in GERD questionnaire (GERDQ) scores, endoscopic Los Angeles (LA) grade, flap valve grade (FVG) based on Hill’s type, EndoFLIP distensibility index (DI), endoscopic Barrett’s epithelium (BE) resolution rate, and PPI withdrawal rate were compared between the two groups. Results: Improvements in the GERDQ scores and PPI withdrawal rates were similar between the groups. The ARMS group showed significantly better changes in endoscopic LA grade, FVG, and EndoFLIP DI than the SRF group. The complications were more prevalent in the ARMS group than in the SRF group. Conclusions The change in endoscopic LA grade before and after the procedure was significantly higher in the ARMS group than in the SRF group. Significant improvements in endoscopic FVG, BE resolution, and EndoFLIP DI were observed only with the ARMS group.

Background/Aims: This study aimed to evaluate the performance of the Model for End-Stage Liver Disease (MELD) 3.0 for predicting mortality and liver-related complications compared with the Child-Pugh classification, albumin-bilirubin (ALBI) grade, the MELD, and the MELD sodium (MELDNa) score. Methods: We evaluated a multicenter retrospective cohort of incorporated patients with cirrhosis between 2013 and 2019. We conducted comparisons of the area under the receiver operating characteristic curve (AUROC) of the MELD3.0 and other models for predicting 3-month mortality. Additionally, we assessed the risk of cirrhosis-related complications according to the MELD3.0 score. Results: A total of 3,314 patients were included. The mean age was 55.9±11.3 years, and 70.2% of the patients were male. Within the initial 3 months, 220 patients (6.6%) died, and the MELD3.0had the best predictive performance among the tested models, with an AUROC of 0.851, outperforming the Child-Pugh classification, ALBI grade, MELD, and MELDNa. A high MELD3.0score was associated with an increased risk of mortality. Compared with that of the group with a MELD3.0 score <10 points, the adjusted hazard ratio of the group with a score of 10–20 pointswas 2.176, and that for the group with a score of ≥20 points was 4.892. Each 1-point increase inthe MELD3.0 score increased the risk of cirrhosis-related complications by 1.033-fold. The risk of hepatorenal syndrome showed the highest increase, with an adjusted hazard ratio of 1.149, followed by hepatic encephalopathy and ascites. Conclusions The MELD3.0 demonstrated robust prognostic performance in predicting mortality in patients with cirrhosis. Moreover, the MELD3.0 score was linked to cirrhosis-related complications, particularly those involving kidney function, such as hepatorenal syndrome and ascites.