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Juyoung Khwarg,1 Soyoung Lee,1,2 In-Jin Jang,1 Won-Ho Kang,3 Hye Jung Lee,4 Kyu Yeon Kim,4 Ki-Sun Jeong,4 Chongho Won,4 Youn Woong Choi,5 Dae Chul Ha,5 RaeHoon Jung,5 Min-Gu Han,5 Won Tae Jung,6 Kyu-Yeol Nam,6 YeSeul Kim,6 Kyung-Sang Yu,1 Jaeseong Oh1,7 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; 3R&D Center, Korea United Pharm. Inc., Seoul, Republic of Korea; 4Caleb Multilab, Inc., Seoul, Republic of Korea; 5R&D Center, Korea United Pharm.Inc., Sejong, Republic of Korea; 6Global R&D, Korea United Pharm. Inc., Seoul, Republic of Korea; 7Department of Pharmacology, Jeju National University College of Medicine, Jeju, Republic of KoreaCorrespondence: Jaeseong Oh, Department of Pharmacology, Jeju National University College of Medicine, 15, Aran 13-gil, Jeju-si, Jeju-do, 63241, Republic of Korea, Email jaeseong5@jejunu.ac.krPurpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects.Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters.Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054– 1.1883) and 0.9885 (0.9588– 1.0192) for atorvastatin, 0.9607 (0.9068– 1.0178) and 0.9770 (0.9239– 1.0331) for EPA, and 0.9961 (0.9127– 1.0871) and 0.9634 (0.8830– 1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated.Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia. Keywords: pharmacokinetics, cardiovascular disease

Objective: To identify the different uses and modalities of digital technologies to diagnose, plan and monitor peri-implant soft tissue conditions and aesthetics., Methods: A comprehensive narrative review of pertinent literature was conducted, critically appraising key digital technologies that may assist peri-implant soft tissue augmentation and assessment. An electronic search on four databases including studies published prior to 1st July 2023 was performed and supplemented by a manual search., Results: Predominantly, tools such as cone beam computed tomography (CBCT), intraoral scanning (iOS), intraoral ultrasonography and digital spectrophotometry were commonly to assess and monitor peri-implant soft tissues. The main clinical and research applications included: (i) initial assessment of mucosal thickness, supra-crestal tissue height and keratinized mucosa width, (ii) evaluation of peri-implant soft tissue health and inflammation, (iii) monitoring profilometric changes and midfacial mucosal margin stability over time and (iv) aesthetic evaluation through colour assessment. While evidence for some digital tools may be limited, the integration of digital technologies into peri-implant soft tissue management holds great promise. These technologies offer improved precision, comfort and speed in assessment, benefiting both patients and clinicians., Conclusion: As digital technologies progress, their full potential in peri-implant soft tissue augmentation and their value will become more evident with ongoing research. Embracing these innovations and their potential benefits is recommended to ensure that during progress in implant dentistry, patient care is not hindered., (© 2024 The Authors. Clinical Oral Implants Research published by John Wiley & Sons Ltd.)

Introduction: Childhood cancer survivors (CCS) are at risk of experiencing lower quality-of-life, fatigue, and depression. Few randomized controlled trials have studied the effect of physical activity (PA) on these in adult long-term CCS. This study investigated the effect of a 1-year individualized PA intervention on health-related quality-of-life (HRQOL), fatigue, and distress symptoms in adult CCS., Methods: The SURfit trial randomized 151 CCS ≥16 years old, <16 at diagnosis and ≥5 years since diagnosis, identified through the Swiss Childhood Cancer Registry. Intervention participants received personalized PA counselling to increase intense PA by ≥2.5 h/week for 1 year. Controls maintained usual PA levels. The authors assessed physical- and mental-HRQOL, fatigue, and distress symptoms at baseline, 3, 6, and 12 months. T-scores were calculated using representative normative populations (mean = 50, standard deviation = 10). Generalized linear mixed-effects models with intention-to-treat (ITT, primary), and three per-protocol allocations were used., Results: At 12 months, ITT (-3.56 larger decrease, 95% confidence interval -5.69 to -1.43, p = .001) and two per-protocol analyses found significantly lower fatigue. Physical-HRQOL improved significantly in two per-protocol analyses at 12 months. No other effects were found., Conclusion: SURfit showed that increased intense PA over 1 year improved fatigue in adult CCS. Survivors should be recommended PA to reduce the burden of late-effects., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: To investigate the changes in retinal arterial architecture after treatment with voretigene neparvovec in patients with retinal dystrophy caused by bi-allelic mutations in the RPE65 gene., Methods: Sixteen eyes treated with voretigene neparvovec at the University Eye Clinic in Tuebingen, Germany, underwent adaptive optics ophthalmoscopy (AO) imaging at baseline and 2 weeks, 1, 3, 6 and 12 months after treatment. Follow-up was performed in six eyes of four patients. For each eye, five different positions at arterial vessels were selected and the wall-to-lumen ratio (WLR), the lumen diameter (LD) and the wall cross-sectional area (WCSA) were measured by the manufacturer's software over the observational period., Results: Vast retinal atrophy dominated all gained AO images. WLR fluctuated in the observation period without statistically significant change. LD and WCSA changed significantly after 2 weeks from the baseline examination and returned to values similar to baseline thereafter. There were no signs of inflammation such as macrophages or perivascular accumulated fluid visible., Conclusion: AO imaging of the retinal vessels in RPE65-associated retinal dystrophies (IRD) is challenging. There was no change in the retinal arterial vasculature over the observation period of 12 months that would indicate inflammatory changes. Decrease of the LD and WCSA shortly after treatment might be caused by the perioperative prednisolone intake. AO of retinal vessels can be used as a diagnostic module to complement monitoring the disease and effects of genetic treatments if the acquisition is possible in selected cases., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Objective: The purpose of this study was to evaluate the age-dependency of amplitudes and implicit times in the electroretinograms (ERGs) of healthy individuals and provide clinicians and researchers with a reference for a variety of stimulus paradigms., Design and Methods: Full-field electroretinography was conducted on 73 healthy participants aged 14-73 using an extended ISCEV standard protocol that included an additional 9 Hz flicker stimulus for assessing rod function and special paradigms for isolated On-Off and S-cone responses. Correlation coefficients and best-fit regression models for each parameter's age-dependency were calculated., Results: Dark-adapted ERGs, in particular, displayed notable age-related alterations. The attenuation and delay of the b-wave with higher age were most significant in the dark-adapted, rod-driven 0.001 cd s/m 2 flash ERG. The age-dependent reduction of the a-wave amplitude was strongest in the standard dark-adapted 3 cd s/m 2 flash condition. Cone-driven, light-adapted responses to either flash or flicker stimuli displayed comparatively small alterations at higher age. S-cone function tended to diminish at an early age, but the effect was not significant in the whole population., Conclusion: The results suggest that rod and cone function decline at different rates with age, with rods being generally more affected by aging. Nonetheless, response amplitudes displayed a wide variability across the whole sample., (© 2024. The Author(s).)

Aim: To investigate whether transmucosal healing is as effective as submerged healing in terms of buccal bone regeneration when guided bone regeneration (GBR) is performed simultaneously with implant placement., Materials and Methods: In six dogs, buccal dehiscence defects were created in the edentulous mandibular ridge, sized 5 × 5 × 3 mm (length × height × depth). In each defect, a bone-level implant was placed, and four experimental groups were randomly assigned as follows: (i) transmucosal healing with GBR (T-GBR), (ii) transmucosal healing without GBR (T-control), (iii) submerged healing with GBR (S-GBR) and (iv) submerged healing without GBR (S-control). Data analyses were based on histological slides 5 months after implant placement., Results: The T-GBR group showed significant differences compared to the control groups regarding defect height resolution, buccal bone thickness and mineralized tissue area (p < .05), but showed no significant differences when compared with the S-GBR group (p > .05)., Conclusions: The mode of healing (transmucosal vs. submerged) does not influence bone regeneration at implant sites. The clinician may therefore choose the approach based on further clinical and patient-specific parameters., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Coherent diffraction imaging (CDI) in the extreme ultraviolet has become an important tool for nanoscale investigations. Laser-driven high harmonic generation (HHG) sources allow for lab scale applications such as cancer cell classification and phase-resolved surface studies. HHG sources exhibit excellent coherence but limited photon flux due poor conversion efficiency. In contrast, table-top soft X-ray lasers (SXRL) feature excellent temporal coherence and extraordinary high flux at limited transverse coherence. Here, the performance of a SXRL pumped at moderate pump energies is evaluated for CDI and compared to a HHG source. For CDI, a lower bound for the required mutual coherence factor of |μ 12| ≥ 0.75 is found by comparing a reconstruction with fixed support to a conventional characterization using double slits. A comparison of the captured diffraction signals suggests that SXRLs have the potential for imaging micron scale objects with sub-20 nm resolution in orders of magnitude shorter integration time compared to a conventional HHG source. Here, the low transverse coherence diameter limits the resolution to approximately 180 nm. The extraordinary high photon flux per laser shot, scalability towards higher repetition rate and capability of seeding with a high harmonic source opens a route for higher performance nanoscale imaging systems based on SXRLs.

Objective &#xD;To investigate the feasibility of delivering multidimensional feedback using a single channel of peripheral nerve stimulation by complementing intensity percepts with flutter frequency percepts controlled by burst period modulation. &#xD; Approach &#xD;Two dimensions of a distally referred sensation were provided simultaneously: intensity was conveyed by the modulation of the pulse charge rate inside short discrete periods of stimulation referred to as bursts and frequency was conveyed by the modulation of the period between bursts. For this approach to be feasible, intensity percepts must be perceived independently of frequency percepts. Two experiments investigated these interactions. A series of two alternative forced choice tasks (2AFC) were used to investigate burst period modulation's role in intensity discernibility. Magnitude estimation tasks were used to determine any interactions in the gradation between the frequency and intensity percepts. &#xD; Main Results &#xD;The 2AFC revealed that burst periods can be individually differentiated as a gradable frequency percept in peripheral nerve stimulation. Participants could correctly rate a perceptual scale of intensity and frequency regardless of the value of the second, but the dependence of frequency differentiability on charge rate indicates that frequency was harder to detect with weaker intensity percepts. The same was not observed in intensity differentiability as the length of burst periods did not significantly alter intensity differentiation. These results suggest multidimensional encoding is a promising approach for increasing information throughput in sensory feedback systems if intensity ranges are selected properly.&#xD; Significance &#xD;This study offers valuable insights into haptic feedback through the peripheral nervous system and demonstrates an encoding approach for neural stimulation that may offer enhanced information transfer in virtual reality applications and sensory-enabled prosthetic systems. This multidimensional encoding strategy for sensory feedback may open new avenues for enriched control capabilities., (Creative Commons Attribution license.)

Objective: To investigate the efficacy of ribose-crosslinked collagen (RCLC) matrices functionalized by crosslinked hyaluronic acid (xHya) for reconstructive treatment of class I and III (b-c) peri-implantitis lesions in a transmucosal healing mode., Materials and Methods: Thirteen patients presenting with 15 implants were included in this prospective case series. Upon flap reflection, the implants were thoroughly decontaminated employing glycine powder air polishing and adjunctive sodium hypochlorite. For defect augmentation, xHyA was administered to the bony defect walls, exposed implant surfaces, and the RCLC matrix before defect grafting. The full-thickness flap was readapted and sutured around the implant neck for transmucosal healing. Baseline and respective values at the 12 months post-op evaluation were recorded for the clinical parameters peri-implant probing depth (PPD), buccal soft tissue dehiscence (BSTD) and bleeding on probing (BoP). Furthermore, two independent investigators analyzed radiographic changes in the defect area. The mean changes for all variables were analyzed with a paired t-test., Results: The initial mean PPD was 7.2 ± 1.9 mm, and BoP was present in 63% of sites. After 12 months, PPD at the latest visit was 3.2 ± 0.66 mm, which amounted to a respective 3.9 ± 1.85 mm reduction, while the BoP frequency dropped to 10% at all sites. Radiographic bone fill was accomplished for 62.8% of the former defect area, accompanied by a mean MBL gain of 1.02 mm around the treated implants (all p < 0.001)., Conclusions: Within the limits of this case series, we conclude that the proposed treatment sequence substantially improved peri-implant defects and offered a simplified but predictive technique., Clinical Relevance: Reconstructive treatment approaches for peri-implantitis are effective but remain non-superior to open flap debridement. Further research on novel biomaterial combinations that may improve reconstructive treatment outcomes are warranted. Ribose-crosslinked collagen matrices biofunctionalized by hyaluronic acid used in this study yield improved clinical and radiographic peri-implant conditions after 12 months., (© 2024. The Author(s).)

Objective: To digitally evaluate the three-dimensional (3D) remodelling of FGG used to treat RT2 gingival recessions and lack of keratinized tissue on mandibular incisor teeth., Methods: Data from 45 patients included in a previous multicentric RCT were analyzed. Silicone impressions were taken before (baseline) and 3, 6 and 12 months after standardized FGG placement. Casts were scanned and images were superimposed, using digital software, to obtain measurements of estimated soft tissue thickness (eTT; 1, 3, and 5 mm apical to baseline gingival margin). In addition, soft tissue volume (STV) and creeping attachment (CA) were assessed., Results: All patients exhibited postoperative eTT and STV increases, at all time points. The greatest mean thickness gain was observed at eTT3 (1.0 ± 0.4 mm) at 12 months. At 12 months, STV was 52.3 ± 21.1 mm 3 , without relevant changes compared to the 3- and 6-month follow-up. CA, which was observed as early as six months postoperatively, was evident in ∼85 % of teeth at 12 months., Conclusions: Application of FGG was an effective phenotype modification therapy, as shown by the significantly increased tissue thickness postoperatively. Despite the use of FGG technique not aiming for root coverage, digital 3D assessment documented the early and frequent postoperative occurrence of CA, which helped improve recession treatment outcomes., Clinical Significance: The use of 3D assessment methodology allows precise identification of the tissue gain obtained with FGG, which, regardless of technique, results in predictable phenotype modification and frequent occurrence of creeping attachment., 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 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate clinical, clinician- and patient-reported outcomes (PROs) of two adjacent single posterior implants immediately loaded with definitive single crowns up to 1 year. Ten patients in need of two adjacent posterior single implants were included. All implants were placed applying a fully digital workflow. Definitive screw-retained single zirconia crowns were delivered within 72 h after implant placement. Clinical parameters, patient- and clinician-reported outcomes were assessed up to 1 year of follow-up., Clinical Considerations: Clinical outcomes remained stable, with no implant failures or technical and biological complications throughout the observation period. Patient satisfaction was very high at baseline (crown delivery) and remained consistently high at 6 and 12 months of follow-up. Crown insertion 3 days after implant placement was rated as an easy procedure by clinicians., Conclusions: Two adjacent single implants with immediate definitive restorations (<72 h) in the posterior region appear to be a viable and easy treatment option to shorten the overall treatment time and potentially enhancing patient satisfaction. However, randomized controlled trials are needed to confirm the advantages of this treatment protocol over a delayed loading approach., Clinical Significance: In selected cases, immediate implant loading with definitive restorations in the posterior region appears a valuable and straightforward option to shorten the overall treatment time., (© 2024 The Authors. Journal of Esthetic and Restorative Dentistry published by Wiley Periodicals LLC.)

Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Fertility preservation in the cancer setting, known as oncofertility, is a field that requires cross-disciplinary interaction between physicians, basic scientists, clinical researchers, ethicists, lawyers, educators, and religious leaders. Funded by the National Institutes of Health, the Oncofertility Consortium (OC) was formed to be a scientifically grounded, transparent, and altruistic resource, both intellectual and monetary, for building this new field of practice capable of addressing the unique needs of young patients with cancer. The OC has expanded its attention to include other nonmalignant conditions that can threaten fertility, and the work of the OC now extends around the globe, involving partners who together have created a community of shared effort, resources, and practices. The OC creates materials that are translated, disseminated, and amended by all participants in the field, and local programs of excellence have developed worldwide to accelerate the pace and improve the quality of oncofertility research and practice. Here we review the global oncofertility programs and the capacity building activities that strengthen these research and clinical programs, ultimately improving patient care.

Percutaneous coronary intervention (PCI) is a management strategy for symptomatic obstructive coronary artery disease (CAD). Despite advancements, in-stent restenosis (ISR) still imparts a 1-2% annual rate of repeat revascularization-a focus of ongoing translational research. Optical coherence tomography (OCT) provides high resolution virtual histology of stents. Our study evaluates the use of OCT for virtual histological assessment of stent healing in a rabbit aorta model, enabling complete assessment of intraluminal healing throughout the stent. ISR varies based on intra-stent location, stent length, and stent type in a rabbit model-important considerations for translational experimental design. Atherosclerosis leads to more prominent ISR proliferation independent of stent-related factors. The rabbit stent model mirrors clinical observations, while OCT-based virtual histology demonstrates utility for pre-clinical stent assessment. Pre-clinical models should incorporate clinical and stent factors as feasible to maximize translation to clinical practice., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)