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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

Abstract Background Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. Methods From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3–5) and gastrointestinal (GI) bleeding (BARC types 3–5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. Results Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18–8.78). The incidence of major bleeding and GI bleeding (BARC types 3–5) was comparable between PPI users and non-users in the PS-matched cohort. Conclusions In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.

Background Aging leads to sarcopenia, which is characterized by reduced muscle mass and strength. Many factors, including altered muscle protein turnover, diminished neuromuscular function, hormonal changes, systemic inflammation, and the structure and composition of muscle fibers, play a crucial role in age-related muscle decline. This study explored differences in muscle fiber types contributing to overall muscle function decline in aging, focusing on individuals with hip fractures from falls. Methods A pilot study at Chungnam National University Hospital collected muscle biopsies from hip fracture patients aged 20 to 80 undergoing surgical treatment. Muscle biopsies from the vastus lateralis and gluteus maximus were obtained during hip arthroplasty or internal fixation. Handgrip strength, calf and thigh circumference, and bone mineral density were evaluated in individuals with hip fractures from falls. We analyzed the relationships between each clinical characteristic and muscle fiber type. Results In total, 26 participants (mean age 67.9 years, 69.2% male) were included in this study. The prevalence of sarcopenia was 53.8%, and that of femoral and lumbar osteoporosis was 19.2% and 11.5%, respectively. Vastus lateralis analysis revealed an age-related decrease in type IIx fibers, a higher proportion of type IIa fibers in women, and an association between handgrip strength and type IIx fibers in men. The gluteus maximus showed no significant correlations with clinical parameters. Conclusion This study identified complex associations between age, sex, handgrip strength, and muscle fiber composition in hip fracture patients, offering insights crucial for targeted interventions combating age-related muscle decline and improving musculoskeletal health.

Objectives Tegoprazan, a novel potassium-competitive acid blocker with rapid and effective antisecretory activity, was approved for the treatment of Helicobacter pylori infections in Korea in March 2020. However, real-world data regarding tegoprazan-based therapies are scarce. We compared the efficacies of tegoprazan- and lansoprazole-based triple therapies (TTs). Methods Between March 2020 and February 2023, this study enrolled patients diagnosed with H. pylori infections who were prescribed either 14-day tegoprazan- or lansoprazole-based TTs as first-line treatments. Their medical records were retrospectively reviewed to compare H. pylori eradication rates and the rates of patient adherence to the recommended therapy. Results A total of 670 patients diagnosed with H. pylori infections were prescribed 14-day TT regimens between March 2020 and February 2023 at Ilsan Paik Hospital (Goyang, Korea). Of those enrolled in the study, 64 received tegoprazan-based TT and 295 received lansoprazole-based TT as their first-line treatment. The H. pylori eradication rates for tegoprazan- and lansoprazole-based TTs were 76.6% and 75.6%, respectively, in the intent-to-treat population; the rates were 88.9% and 88.4%, respectively, in the per-protocol population (non-inferiority test, p=0.03 and p=0.01 in the respective populations). No significant differences were observed between the two groups with regards to treatment adherence rates (84.4% vs. 85.1%, p=0.78). Conclusions As a first-line treatment for H. pylori eradication, 14-day tegoprazan-based TT demonstrated non-inferior efficacy compared with 14-day lansoprazole-based TT.

Abstract This study evaluated the association of atherogenic index of plasma (AIP) with platelet reactivity and clinical outcomes according to acute myocardial infarction (AMI). The composite of 3-year adverse outcomes of all-cause death, myocardial infarction, and cerebrovascular accident was evaluated in 10,735 patients after successful percutaneous coronary intervention with drug-eluting stents. AIP was defined as the base 10 logarithm of the ratio of triglyceride to high-density lipoprotein cholesterol concentration. High platelet reactivity (HPR) was defined as ≥ 252 P2Y12 reactivity unit. An increase of AIP (per-0.1 unit) was related to the decreased risk of HPR [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.96–0.99; P = 0.001] in non-AMI patients, not in AMI patients (OR 0.98, 95% CI 0.96–1.01; P = 0.138). The HPR was associated with the increased risk of composite outcomes in both non-AMI and AMI patients (all-P

ObjectiveA beneficial effect on endometrial thickness (EMT) and improvement of pregnancy outcome after intrauterine infusion of platelet-rich plasma (PRP) has been suggested. This study assessed the effect of intrauterine PRP infusion on live birth rate and obstetrical outcomes and analyzed cytokines that can potentially improve pregnancy outcomes through PRP.MethodThis study was a prospective cohort study conducted in a university hospital fertility center. The study included ninety-one patients who had a history of two or more failed in vitro fertilization (IVF) attempts and refractory thin endometrium that remained unresponsive after at least two conventional treatments for thin endometrium. Patients were treated with an intrauterine infusion of autologous PRP between days 7 and 14 of their hormone replacement therapy-frozen embryo transfer (HRT-FET) cycle. PRP was administered at 3-day intervals until their EMT reached 7mm. After a maximum of three PRP administrations, embryo transfer (ET) was performed. The primary outcome was the live birth rate. Secondary outcomes included the implantation rate and increase in EMT compared to the previous cycle. We compared the cytokines related to angiogenesis in a patient’s whole blood (WB) and PRP by utilizing a commercial screening kit.ResultsThe live birth rate in the PRP treatment cycle was 20.9% (19 of 91 patients), significantly superior to the previous cycle without PRP infusion (p < 0.001). The implantation rate was also significantly higher during the PRP treatment cycle (16.4%) compared to the previous cycle (3.1%) (p < 0.001). The mean EMT post-PRP treatment was 6.1 mm, showing a significant increase of 0.8 mm (p < 0.001). Nonetheless, an increase in EMT was also observed in the non-pregnancy group. No adverse effects were reported by patients treated with autologous PRP. Cytokine array analysis confirmed marked increases in well-known pro-angiogenic factors such as Ang-1, EGF, LAP (TGF-b1), MMP-8, PDGF-AA, and PDGF-AB/PDGF-BB.ConclusionIntrauterine PRP infusion offers a safe and effective treatment for patients with refractory thin endometrium and implantation failures. The angiogenic cytokines present in PRP are the primary drivers of this improvement.

Fossil resources must be replaced by renewable resources in production systems to mitigate green-house gas emissions and combat climate change. Electro-fermentation utilizes a bioelectrochemical system (BES) to valorize industrial and municipal waste. Current electro-fermentation research is mainly focused on microbial electrosynthesis using CO2 for producing commodity chemicals and replacing petroleum-based infrastructures. However, slow production rates and low titers of metabolites during CO2-based microbial electrosynthesis impede its implementation to the real application in the near future. On the other hand, CO is a highly reactive gas and an abundant feedstock discharged from fossil fuel-based industry. Here, we investigated CO and CO2 electro-fermentation, using a CO-enriched culture. Fresh cow fecal waste was enriched under an atmosphere of 50% CO and 20% CO2 in N2 using serial cultivation. The CO-enriched culture was dominated by Clostridium autoethanogenum (≥89%) and showed electro-activity in a BES reactor with CO2 sparging. When 50% CO was included in the 20% CO2 gas with 10 mA applied current, acetate and ethanol were produced up to 12.9 ± 2.7 mM and 2.7 ± 1.1 mM, respectively. The coulombic efficiency was estimated to 148% ± 8% without an electron mediator. At 25 mA, the culture showed faster initial growth and acetate production but no ethanol production, and only at 86% ± 4% coulombic efficiency. The maximum optical density (OD) of 10 mA and 25 mA reactors were 0.29 ± 0.07 and 0.41 ± 0.03, respectively, whereas it was 0.77 ± 0.19 without electric current. These results show that CO electro-fermentation at low current can be an alternative way of valorizing industrial waste gas using a bioelectrochemical system.

Background Carriers of CYP2C19 loss‐of‐function alleles have increased adverse events after percutaneous coronary intervention, but limited data are available for older patients. We aimed to evaluate the prognostic impact of CYP2C19 genotypes on clinical outcomes in older patients after percutaneous coronary intervention. Methods and Results The study included 1201 older patients (aged ≥75 years) who underwent percutaneous coronary intervention and received clopidogrel‐based dual antiplatelet therapy in South Korea. Patients were grouped on the basis of CYP2C19 genotypes. The primary outcome was 3‐year major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and stent thrombosis. Older patients were grouped into 3 groups: normal metabolizer (36.6%), intermediate metabolizer (48.1%), and poor metabolizer (15.2%). The occurrence of the primary outcome was significantly different among the groups (3.1, 7.0, and 6.2% in the normal metabolizer, intermediate metabolizer, and poor metabolizer groups, respectively; P=0.02). The incidence rate of all‐cause death at 3 years was greater in the intermediate metabolizer and poor metabolizer groups (8.1% and 9.2%, respectively) compared with that in the normal metabolizer group (3.5%, P=0.03) without significant differences in major bleeding. In the multivariable analysis, the intermediate metabolizer and poor metabolizer groups were independent predictors of 3‐year clinical outcomes. Conclusions In older patients, the presence of any CYP2C19 loss‐of‐function allele was found to be predictive of a higher incidence of major adverse cardiac events within 3 years following percutaneous coronary intervention. This finding suggests a need for further investigation into an optimal antiplatelet strategy for older patients. Registration URL: https://clinicaltrials.gov. Identifier: NCT04734028.

Background Although age and body mass index (BMI) significantly affect platelet reactivity units and clinical outcomes after percutaneous coronary intervention, there are limited data on the relationship between high on‐treatment platelet reactivity (HPR) and clinical outcomes on age and BMI differences. Thus, we investigated the association of HPR with clinical outcomes according to age and BMI. Methods and Results The study analyzed 11 714 patients who underwent platelet function tests after percutaneous coronary intervention. The primary end point was the occurrence of major adverse cardiac and cerebrovascular events (MACCEs), whereas the secondary end point was major bleeding. HPR was defined as platelet reactivity units ≥252. Patients were categorized by age (22.6 kg/m2). Patients 22.6 kg/m2 had increases in MACCEs (adjusted HR, 1.387 [95% CI, 1.140–1.688]; P=0.001). No differences were shown in major bleeding. Conclusions HPR was linked to an increase in MACCEs or a decrease in major bleeding in patients after percutaneous coronary intervention, depending on age and BMI. This study is the first to observe that clinical outcomes in patients with HPR after percutaneous coronary intervention may vary based on age and BMI. Because the study is observational, the results should be viewed as hypothesis generating and emphasize the need for randomized clinical trials.

Abstract Stent thrombosis (ST) is a fatal complication after percutaneous coronary intervention (PCI). The association between P2Y12 reaction unit (PRU) level and stent thrombosis occurrence remains unclear. Based on the multicenter, observational PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) registry of patients with drug-eluting stents (DES) implantation, a total of 11,714 patients with PRU values were analyzed. We sought to identify the predictors of early stent thrombosis (EST) and compared the primary outcome, a composite of cardiac death, myocardial infarction, and revascularization, between EST and non-EST groups. EST, defined as definite ST within 1 month after index PCI, occurred in 51 patients. PRU values were significantly higher in the EST group (263.5 ± 70.8 vs. 217.5 ± 78.7, p

Obtaining symmetrical and highly linear synapse weight update characteristics of analog resistive switching devices is critical for attaining high performance and energy efficiency of the neural network system. In this work, based on the two-terminal one transistor-one memristor (1T1M) block, the improvement of the symmetry and linearity of synaptic weight update is demonstrated by combining the InGaZnO synaptic transistor and memristor. Due to the symmetric and linear weight update characteristic, a pattern recognition accuracy of 88% is achieved after 50 epochs in the on-chip learning simulation of the hand-written digit images (MNIST) data set. The proposed 1T1M device saves the hardware burden and additional power consumption required to implement non-identical programming pulses.

Background: Reduced-port robotic myomectomy (RPRM) using Da Vinci® Xi™ is a good fertility-saving surgical option, but the surgical and fertility outcomes are unknown. Methods: This was a retrospective cohort study evaluating the feasibility of RPRM in an academic tertiary hospital setting. A total of 401 patients who underwent RPRM by a single operator between October 2017 and October 2021 were included. For RPRM, three ports are required: a 1.5 cm umbilical incision and two 0.8 cm incisions 8 cm lateral to the umbilicus. A single-port system was applied through the umbilicus, which also functioned as a working port. Unlike conventional robotic surgery, only three robot arms were utilized for the entire surgical procedure. Results: Surgical and fertility outcomes were assessed through medical records review and follow-up telephone contact. The mean age of patients at the time of surgery was 39.7 ± 6.0 years. The most common indication for surgery was menorrhagia (n = 128, 31.9%). The average number of myomas removed was 4.7 ± 4.1 (1–22), and the size was 7.8 ± 2.5 cm (2.5–16.0). The mean operation time was 103.7 ± 45.6 min. Postoperative complications were found in 9.7% (n = 39) of patients; the most common complication was transfusion (7.7%, n = 31). After surgery, 70 patients tried to conceive, and 56 became pregnant naturally or by assisted reproduction (56/70, 80.0%). The mean interval time from operation to conception was 13.5 ± 10.1 months. Among 56 who conceived, 44 gave birth (62.9%), five were still ongoing (7.1%), and seven had miscarriages (10.0%). Cesarean section was performed for most cases (43/44, 97.7%). Eight patients had obstetric complications (16.3%), but no uterine rupture was reported. Conclusions: RPRM, which provides the benefits of conventional robotic surgery along with favorable obstetric and cosmetic results, is a feasible option for patients with symptomatic uterine myomas who wish to conceive in the future.

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: 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).)

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.)

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.)

Over the past several centuries, the integration of contemporary medical techniques and innovative technologies, like genetic sequencing, have played a pivotal role in enhancing our comprehension of congenital vascular and lymphatic disorders. Nonetheless, the uncommon and complex characteristics of these disorders, especially considering their formation during the intrauterine stage, present significant obstacles in diagnosis and treatment. Here, we review the intricacies of these congenital abnormalities, offering an in-depth examination of key diagnostic approaches, genetic factors, and therapeutic methods., Competing Interests: Disclosures None.

Aims: The cytokine interleukin-6 (IL-6) plays a central role in the inflammation cascade as well as cardiovascular disease progression. Since myeloid cells are a primary source of IL-6 formation, we aimed to generate a mouse model to study the role of myeloid cell-derived IL-6 in vascular disease., Methods and Results: Interleukin-6-overexpressing (IL-6 OE ) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6 OE mice) overexpressing the cytokine in myeloid cells. Eight- to 12-week-old LysM-IL-6 OE mice spontaneously developed inflammatory colitis and significantly impaired endothelium-dependent aortic relaxation, increased aortic reactive oxygen species (ROS) formation, and vascular dysfunction in resistance vessels. The latter phenotype was associated with decreased survival. Vascular dysfunction was accompanied by a significant accumulation of neutrophils, monocytes, and macrophages in the aorta, increased myeloid cell reactivity (elevated ROS production), and vascular fibrosis associated with phenotypic changes in vascular smooth muscle cells. In addition to elevated Mcp1 and Cxcl1 mRNA levels, aortae from LysM-IL-6 OE mice expressed higher levels of inducible NO synthase and endothelin-1, thus partially accounting for vascular dysfunction, whereas systemic blood pressure alterations were not observed. Bone marrow (BM) transplantation experiments revealed that vascular dysfunction and ROS formation were driven by BM cell-derived IL-6 in a dose-dependent manner., Conclusion: Mice with conditional overexpression of IL-6 in myeloid cells show systemic and vascular inflammation as well as endothelial dysfunction. A decrease in circulating IL-6 levels by replacing IL-6-producing myeloid cells in the BM improved vascular dysfunction in this model, underpinning the relevant role of IL-6 in vascular disease., Competing Interests: Conflict of interest: M.B. received funding and is a consultant for ARCA Biopharma (not related to the presented work). S.K. received funding for consultant lectures from Almiral and Jansson-Cilag (not related to the presented work either)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Bladder cancer (BC) is the 12th most commonly diagnosed cancer worldwide. Although there are several well-established molecular and immunological classifications, prognostic and predictive markers for tumor cells and immune cells are still needed. Using a tissue microarray, we analyzed the expression of the chemokine CC motif ligand 5 (CCL5) by immunohistochemistry (IHC) in 175 muscle-invasive BC samples. The application of a single cutoff for the staining status of tumor cells (TCs; positive vs. negative) and immune cells (ICs; positive vs. negative) revealed 75 patients (42.9%) and 123 patients (70.3%) with CCL5-positive TCs or ICs, respectively. IHC results were associated with prognostic and predictive data. Multivariate Cox regression analysis revealed that positive CCL5 staining in TCs was associated with significantly shorter disease-specific survival (DSS; RR = 1.51; p = 0.047), but CCL5-negative ICs were associated with significantly shorter overall survival (OS; RR = 1.66; p = 0.005), DSS (RR = 2.02; p = 0.001) and recurrence-free survival (RFS; RR = 1.94; p = 0.002). Adjuvant chemotherapy was favorable for patients with CCL5-negative ICs for OS (RR = 0.30; p = 0.006), DSS (RR = 0.36; p = 0.022) and RFS (RR = 0.41; p = 0.046) but not for patients with CCL5-positive ICs, except in the subgroup of N1 + N2 patients, where it was associated with better OS. We suggest that CCL5 expression can be a prognostic and predictive marker for muscle-invasive bladder cancer patients.

Purpose: Investigating influencing factors on the pupillary light response (PLR) as a biomarker for local retinal function by providing epidemiological data of a large normative collective and to establish a normative database for the evaluation of chromatic pupil campimetry (CPC)., Methods: Demographic and ophthalmologic characteristics were captured and PLR parameters of 150 healthy participants (94 women) aged 18 to 79 years (median = 46 years) were measured with L-cone- and rod-favoring CPC protocols. Linear-mixed effects models were performed to determine factors influencing the PLR and optical coherence tomography (OCT) data were correlated with the pupillary function volume., Results: Relative maximal constriction amplitude (relMCA) and latency under L-cone- and rod-favoring stimulation were statistically significantly affected by the stimulus eccentricity (P < 0.0001, respectively). Iris color and gender did not affect relMCA or latency significantly; visual hemifield, season, and daytime showed only minor influence under few stimulus conditions. Age had a statistically significant effect on latency under rod-specific stimulation with a latency prolongation ≥60 years. Under photopic and scotopic conditions, baseline pupil diameter declined significantly with increasing age (P < 0.0001, respectively). Pupillary function volume and OCT data were not correlated relevantly., Conclusions: Stimulus eccentricity had the most relevant impact on relMCA and latency of the PLR during L-cone- and rod-favoring stimulation. Latency is prolonged ≥60 years under scotopic conditions. Considering the large study collective, a representative normative database for relMCA and latency as valid readout parameters for L-cone- and rod-favoring stimulation could be established. This further validates the usability of the PLR in CPC as a biomarker for local retinal function.

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.)

Background/objectives: This study investigated the relationship between adherence to the Mediterranean diet among Korean baby boomers and their levels of psychosocial stress., Subjects/methods: The study included 1,656 adults (889 men and 797 women) born between 1955 and 1963 who participated in the 2005-2006 survey of the community-based Korean Genome and Epidemiology Study (KoGES). The Mediterranean-type diet score (MTDS) was calculated from the semi-quantitative food frequency questionnaire (SQFFQ) data. The psychosocial stress levels were calculated using the psychosocial well-being index-short form (PWI-SF). Logistic regression analyses were performed to analyze the association between the MTDS (tertiles) and the prevalence of high psychosocial stress by gender., Results: The ranges of the MTDS tertile groups were T1 (20-33 points), T2 (34-37 points), and T3 (38-39 points) for men, T1 (20-33 points), T2 (34-37 points), and T3 (38-48 points) for women. In both men and women, the consumption of whole grains, potatoes, fruits, vegetables, legumes, and fish increased with higher MTDS, while the consumption of red meat and dairy products decreased ( P for trend < 0.05). As MTDS score increased the intake of energy, fiber, vitamins, and minerals ( P for trend < 0.05). Men in the highest MTDS tertile had a 41% lower odds ratio (OR) of high psychosocial stress compared with those in the lowest tertile (OR, 0.59; 95% confidence interval [CI], 0.38-0.91). Similarly, women in the highest tertile of the MTDS had a 39% lower OR of high psychosocial stress compared with those in the lowest tertile (OR, 0.61; 95% CI, 0.40-0.95)., Conclusion: Promoting adherence to the Mediterranean diet among baby boomers may have a positive impact on reducing their levels of psychosocial stress., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2024 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Objectives: To assess both the radiographic and profilometric outcomes of early implant placement with or without alveolar ridge preservation (ARP) (using two different ARP techniques) after 1 year of loading., Materials and Methods: Seventy-five patients with a failing single tooth in the anterior maxilla were randomly allocated to three groups (1:1:1): (a) ARP using demineralized bovine bone mineral containing 10% collagen (DBBM-C) covered by a collagen matrix (CM), (b) ARP using DBBM-C covered with a palatal graft (PG), and (c) unassisted socket healing (control). Eight weeks after tooth extraction, early implant placement was performed in all patients. Cone-beam computed tomography (CBCT) and impressions were taken 8 weeks after tooth extraction (ARP/unassisted healing) prior to implant placement and 1-year post-loading. Radiographic and profilometric outcomes were evaluated., Results: Out of the 70 patients available for re-examination at 1-year post-loading, 55 datasets could be assessed (ARP-CM 19; ARP-PG 17; Control 19). The need for additional guided bone regeneration (GBR) at implant placement amounted to 31.6% (ARP-CM), 29.4% (ARP-PG), and 68.4% (unassisted healing). Adjusted models revealed that residual buccal bone height and additional GBR at implant placement significantly influenced the magnitude of the alveolar changes at 1 year (p < 0.05). In patients with ARP (group ARP-CM or ARP-PG) without additional GBR, the presence of bone convexity amounted to 36.0% (9/25) at 1-year post-loading. For patients that received ARP and additional GBR at implant placement, the frequency of bone convexity increased to 72.7% (8/11) (p = 0.042). Regarding profilometric measurements, a tendency toward agreement with radiographic outcomes was observed., Conclusions: Early implant placement with ARP can attenuate alveolar ridge changes at 1-year post loading by minimizing both radiographic and profilometric alterations. However, early implant placement with simultaneous GBR consistently yields superior radiographic and profilometric outcomes, regardless of whether ARP is performed., (© 2023 Wiley Periodicals LLC.)

Purpose: To investigate age-dependent wall to lumen ratio (WLR) reference values for healthy individuals in adaptive optics imaging (AO). WLR serves as an objective, dimensionless parameter for the evaluation of structural changes in vessels caused by conditions like arterial hypertension, diabetes or vascular stenosis., Methods: 50 right eyes of healthy individuals were examined by adaptive optics imaging. The central big arterioles and smaller arterial branches at least one disc diameter away from the optic disc, approximately above or below the macula were measured by the manufacturer's software. The wall-lumen-ratio (WLR), the wall cross-sectional area (WCSA) and lumen diameter (LD) were assessed. Subsequent data analysis was performed with a focus on variables including age, gender and blood pressure., Results: Normative values for WLR, WCSA and LD in 5 different age groups could be established. However, no significant differences between the age groups were found. Intra-subject comparisons revealed significantly higher WLRs on peripheral branches when compared to central arterioles. WLR showed in this normotensive cohort no relevant correlation with the systolic, diastolic and mean blood pressure. Gender and intraocular pressure had no influence on the vascular parameters., Conclusion: AO is capable of examining vascular alterations in arterioles at an almost microscopic level. Age did not seem to alter WLR, normotensive blood pressure parameters showed also no significant impact. AO-based vessel analysis may provide clinically useful biomarkers for cardiovascular health and should be tested in future studies., 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., (Copyright © 2024 Kortuem, Merle, Reith, Kuehlewein, Jung, Holocher, Stingl, Stingl and Kempf.)

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.)

Novel bioelectronic medical devices that target neural control of visceral organs (e.g., liver, gut, spleen) or inflammatory reflex pathways are innovative class III medical devices like implantable cardiac pacemakers that are lifesaving and life-sustaining medical devices. Bringing innovative neurotechnologies early into the market and the hands of treatment providers would benefit a large population of patients inflicted with autonomic and chronic immune disorders. Medical device manufacturers and software developers widely use the Waterfall methodology to implement design controls through verification and validation. In the Waterfall methodology, after identifying user needs, a functional unit is fabricated following the verification loop (design, build, and verify) and then validated against user needs. Considerable time can lapse in building, verifying, and validating the product because this methodology has limitations for adjusting to unanticipated changes. The time lost in device development can cause significant delays in final production, increase costs, and may even result in the abandonment of the device development. Software developers have successfully implemented an Agile methodology that overcomes these limitations in developing medical software. However, Agile methodology is not routinely used to develop medical devices with implantable hardware because of the increased regulatory burden of the need to conduct animal and human studies. Here, we provide the pros and cons of the Waterfall methodology and make a case for adopting the Agile methodology in developing medical devices with physical components. We utilize a peripheral nerve interface as an example device to illustrate the use of the Agile approach to develop neurotechnologies., 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., (Copyright © 2024 Thota and Jung.)

Purpose: Chorioretinal atrophy growth after voretigene neparvovec has been reported recently with its positive correlation with successful treatment. This finding raised the question on long-term effects and the etiology of the chorioretinal atrophy., Methods: Using local retinal functional diagnostics, we tested whether the atrophy growth is connected to the initial local functional improvement after the therapy., Results: The results describe factors predicting the development of atrophy. First, the atrophy emerges after approximately 3 months in an area with local functional rescue before. The areas of the greatest gain in the number of functionally rescued rods are prone to be the initial spots of atrophy growth in almost one-half of the cases and the retinotopy corresponds with the area of a high number of post-treatment functioning rods. Second, the dark-adapted perimetry shows that the atrophy growth is in the area with functioning rescued rods. However, the rods with the greatest sensitivity gain are not the parts of the growing atrophy in the first 2 years after intervention. This preservation of rods with the greatest sensitivity seems to explain the excellent profile of rods rescue over the long term measured by full-field stimulus threshold and reported earlier., Conclusions: A disbalance between the increase of functional rods and their threshold shortly after treatment could be an indicator for a metabolic origin of chorioretinal atrophy after voretigene neparvovec., Translational Relevance: A basic understanding of the photoreceptor rescue aspects after gene therapy can demonstrate a metabolic causal influence of the efficacy on the development of side effects, such as chorioretinal atrophy.

Background: Voretigene neparvovec (Luxturna®) is the first approved gene therapy for RPE65-linked Leber congenital amaurosis (LCA). Though individual effects are highly variable, most recipients report improved vision in everyday life. To describe such effects, visual navigation tests are now frequently used in clinical trials. However, it is still unclear how their results should be interpreted compared to conventional parameters of visual function., Methods: Seven LCA patients underwent a multi-luminance visual navigation test (Ora-VNCTM) before and 3 months after receiving Luxturna gene therapy. Their performance was rated based on the luminance level at which they passed the course. Differences between the first and second test were correlated to changes in visual acuity, full-field stimulus thresholds, chromatic pupil campimetry, and dark-adapted perimetry., Results: A few patients displayed notable improvements in conventional measures of visual function whereas patients with advanced retinal degeneration showed no relevant changes. Independent of these results, almost all participants improved in the visual navigation task by one or more levels. The improvement in the mobility test was best correlated to the change in full-field stimulus thresholds. Other measures of visual functions showed no clear correlation with visual navigation., Discussion: In patients who passed the test's more difficult levels, improved visual navigation can be attributed to the reactivation of rods. However, the performance of patients with low vision seemed to depend much more on confounding factors in the easier levels. In sum, such tests might only be meaningful for patients with better preserved visual functions., (© 2023. The Author(s).)