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COVID-19 vaccine uptake varied across countries, in part due to vaccine hesitancy fueled by a lack of trustworthy information. To help health workers provide evidence-based answers to common questions about COVID-19 vaccines and vaccination, and thereby, assist individuals´ decisions on vaccine acceptance, COVID-19 InfoVaccines, a joint WHO-EU project, was launched in February 2021 to support COVID-19 vaccine rollout in 6 Eastern European countries. COVID-19 InfoVaccines was made available in seven languages and shared on social media networks. A total of 262,592 users accessed COVID-19 InfoVaccines.com between February 11, 2021, and January 31 st , 2023. The users were most interested in: general questions; vaccine efficacy and duration of protection; vaccine safety; vaccine co-administration, and dose-interval and interchangeability; though the interest in a specific theme varied in function of the epidemiological situation. A total of 118,510 (45.1%) and 46,644 (17.7%) users scrolled up to 35% and 75% of the COVID-19 InfoVaccines webpage, respectively. The average engagement rate was 71.61%. The users accessed COVID-19 InfoVaccines from 231 countries and territories, but the majority were in Ukraine ( N  = 38,404; 14.6%), Spain ( N  = 23,327; 8.9%), and Argentina ( N  = 21,167; 8.1%). Older Facebook users were more interested in COVID-19 information than younger individuals ( X p-value < .0001). Two hundred twenty-eight videos were shared on YouTube. The average Click-Through-Rate on Facebook was 7.82%, and that on YouTube was 4.4%, with 60 videos having a Click-Through-Rate >5%, falling in the range of average YouTube video Click-Through-Rate (2% - 10%). As misinformation about vaccines and vaccination spreads easily and can negatively impact health-related decisions, initiatives like COVID-19 InfoVaccines are crucial to facilitate access to reliable information. 2 p-value < .0001). Two hundred twenty-eight videos were shared on YouTube. The average Click-Through-Rate on Facebook was 7.82%, and that on YouTube was 4.4%, with 60 videos having a Click-Through-Rate >5%, falling in the range of average YouTube video Click-Through-Rate (2% - 10%). As misinformation about vaccines and vaccination spreads easily and can negatively impact health-related decisions, initiatives like COVID-19 InfoVaccines are crucial to facilitate access to reliable information.

Nirsevimab has been recently licensed for universal RSV prophylaxis in infants. NIRSE-GAL is a three-year population-based study initiated in Galicia in September 2023. It aims to evaluate nirsevimab effectiveness against RSV-related hospitalizations lower respiratory tract infections (LRTI), severe RSV, all-cause LRTI, and all-cause hospitalization. NIRSE-GAL also aims to estimate nirsevimab impact on primary healthcare use in the short and mid-term, children's wheezing and asthma, and medical prescriptions for RSV. The immunization campaigns will be scheduled based on the expected start week for the RSV season and will last the whole season. Immunization will be offered to: i) infants born during the campaign (seasonal), ii) infants < 6 months at the start of the campaign (catch-up), and iii) infants with high-risk factors, aged 6-24 months at the start of the campaign (high-risk). The follow-up period will start: i) the immunization date for all immunized infants, ii) the start of the campaign, for the non-immunized catch-up or high-risk groups, or iii) the birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of study. Nirsevimab effectiveness will be estimated using Poisson and Cox regression models. Sensitivity and stratified analyses will be undertaken. The number of averted cases and the number needed to immunize will be estimated. Immunization failure and nirsevimab safety will be monitored. NIRSE-GAL was approved by the ethics committee of Galicia (CEIC 2023-377) and registered in ClinicalTrials.gov (ID: NCT06180993). Findings will be mainly shared via peer-reviewed publications and scientific conferences.

Aripiprazole once-monthly (AOM) exhibits an important interindividual pharmacokinetic variability with significant implications for its clinical use. CYP2D6 and CYP3A4 highly contributes to this variability, as they metabolize aripiprazole (ARI) into its active metabolite, dehydroaripiprazole (DHA) and the latter into inactive metabolites. This study aims to evaluate the effect of CYP2D6 and CYP3A4 polymorphisms in combination and the presence of concomitant inducers and inhibitors of this cytochromes on ARI and DHA plasma concentrations in a real clinical setting. An observational study of a cohort of 74 Caucasian patients under AOM treatment was conducted. Regarding CYP2D6, higher concentrations were found for active moiety (ARI plus DHA) (AM) (67 %), ARI (67 %) and ARI/DHA ratio (77 %) for poor metabolizers (PMs) compared to normal metabolizers (NMs). No differences were found for DHA. PMs for both CYP2D6 and CYP3A4 showed a 58 % higher AM and 66 % higher plasma concentration for ARI compared with PMs for CYP2D6 and NMs for CYP3A4. In addition, PMs for both CYP2D6 and CYP3A4 have 45 % higher DHA concentrations than NMs for both cytochromes and 41 % more DHA than PMs for CYP2D6 and NMs for CYP3A4, suggesting a significant role of CYP3A4 in the elimination of DHA. Evaluating the effect of CYPD26 and CYP3A4 metabolizing state in combination on plasma concentrations of ARI, DHA and parent-to-metabolite ratio, considering concomitant treatments with inducers and inhibitor, could optimize therapy for patients under AOM treatment., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To measure the primary care interval (PCI) in the diagnostic delay of oral cancer and to assess the relation of the referring physician's specialty with disease stage at diagnosis., Methods: We meta-analyzed reports of oral/oropharyngeal carcinomas detailing PCI start- and endpoints, i.e., the time needed by a primary care physician to refer a suspected oral cancer patient to a specialist., Results: 17 studies with a total of 2530 patients were eligible; nine provided data on the relative length of PCI, and 10 reported on the impact of the referring professional's specialty on oral cancer diagnostic delay. The average PCI length was slightly longer for general practitioners (GPs) (30.5 days) than for general dental practitioners (GDPs) (27.6 days), while that for the total group was 28.7 days. One-third of the total pre-hospital time spent on diagnosis elapses in GP practices (PCI%: 0.31 [95% CI: 0.23, 0.40]). GDPs refer their patients for treatment at earlier disease stages (TNM I-II) than GPs (Odds Ratio: 0.58; 95% CI: 0.34-0.98)., Conclusions: Primary care accounts for a considerable pre-hospital amount of time of what is necessary for reaching a diagnosis of oral cancer patients. This calls for enhancing early oral cancer recognition in primary care settings., (© 2024 The Author(s). Oral Diseases published by John Wiley & Sons Ltd.)

Background: Catheter ablation of accessory pathway is the treatment of choice for patients with symptomatic Wolff-Parkinson-White (WPW) syndrome. Accessory pathway (AP) identification relies on point-by-point mapping, raising the need for more precise and efficient methods. High-density open window mapping (OWM) combined with the extended early meets late (EEML) algorithm, utilizing 3D electroanatomic mapping systems, is a promising alternative. However, its role in clinical practice lacks comprehensive investigation, necessitating a comparison with conventional mapping., Methods: A prospective cohort study of patients referred for AP ablation evaluated the OWM strategy, comparing it with a retrospective cohort using conventional mapping. Procedure variables, including radiofrequency (RF), fluoroscopy, mapping and procedure times along with total mapping points were compared. Long-term recurrence rates were assessed., Results: 42 patients in the OWM group and 34 in the conventional group were included. The OWM strategy exhibited a significantly lower total mapping time (p = 0.030) despite acquiring more points (p < 0.001) than the conventional group. OWM was associated with reduced fluoroscopy time (12.0 (9.0-16) vs. 19 (11-30) minutes, p = 0.009) and RF time (p = 0.021). Long-term recurrence rates were comparable between groups (7.1% OWM vs. 17.7% conventional mapping, p = 0.284). At a median follow-up of 16.2 (4.6-39.4) months there were not significant differences in recurrence-free survival (p = 0.509)., Conclusion: OWM with the EEML algorithm is a feasible tool for precise AP location and ablation, associated with less fluoroscopy time, RF time, and total mapping time. Long-term recurrence rates were similar to conventional mapping. Prospective studies are warranted for further validation., Competing Interests: Declarations. Competing interests: This work was supported by a grant of Biosense Webster., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Proteins are biological macromolecules well known to regulate many cellular signaling mechanisms. For instance, they are very appealing for their application as therapeutic agents, presenting high specificity and activity. Nonetheless, they suffer from unfolding, instability and low bioavailability making their administration through systemic and other routes very tough. To overcome these drawbacks, drug delivery systems and nanotechnology have arisen to deliver biomolecules in a sustained manner while, at the same time, increasing dose availability, protecting the cargo without compromising proteins' bioactivity, and enhancing intracellular delivery. In this work, we proposed the optimization of sphingomyelin nanosystems (SNs) for the delivery of a wide collection of proteins (ranging from 10-500 kDa and pI) using diverse chemical association strategies. We have further characterized SNs by varied analytical methodologies. We have also carried out in vitro experiments to validate the potential of the developed formulations. As the final goal, we aim to obtain evidence of the potential use of SNs for the development of protein therapeutics., (© 2024 Diversa Technologies SL and The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

Mangroves are coastal hotspots for carbon storage and yet face multiple threats from anthropogenic activities. Here we explore the role of iron-mediated organomineral interactions (FeOMIs) in soil organic carbon (SOC) stabilization and their sensitivity to land use change (LUC) in Amazonian mangroves. We show that Fe oxides protect more labile SOC fractions, which would otherwise be vulnerable to biological degradation, with poorly crystalline Fe oxides being the most effective phase for SOC retention. Despite the fragile equilibrium of FeOMI under dynamic redox conditions in mangroves, this balance sustains approximately 8% of total SOC. The studied LUC scenario led to massive loss of FeOMIs as less crystalline phases were either degraded or transformed into more crystalline ones, losing the efficiency in retaining SOC. The conversion of mangroves to pastures and shrimp ponds, which are pervasive globally, triggers important biogeochemical changes, with major implications for the carbon sequestration potential of mangrove soils., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Statement of Problem: Gingival irritation is a common side effect of at-home bleaching, but how the design of the bleaching tray affects its occurrence is unclear., Purpose: The purpose of this randomized clinical trial was to determine whether a direct relationship is present between the design of bleaching trays and the risk of gingival irritation during at-home bleaching treatments., Material and Methods: This clinical trial was registered at ClinicalTrials.gov. (NCT06371664). Seventy-two participants were randomly assigned to 2 experimental groups: extended bleaching tray (3 mm) and nonextended bleaching tray (1 mm). Over a period of 3 weeks, participants underwent a nightguard dental bleaching treatment (6 to 8 hours) using 16% carbamide peroxide gel. Gingival irritation was evaluated subjectively by participants daily and objectively by clinicians at each visit. Tooth sensitivity was recorded daily using a 5-point numerical scale. Tooth color measurements were also made with a dental spectrophotometer. The risk of gingival irritation and the risk and intensity of tooth sensitivity were analyzed with the Pearson chi squared test and Fisher exact test. The color analysis was conducted with the Student t test (α=.05)., Results: Subjectively, the risk of gingival irritation was 66.7% in the extended group and 47.2% in the nonextended group, showing no statistically significant difference (P>.05). However, objectively, the risk of gingival irritation was significantly higher in the extended group (88.9%) compared with the nonextended group (63.9%) (P=.01(95% CI 1.06 to 1.83). Tooth sensitivity intensity was significantly higher in the extended tray group (P<.001), although the design did not significantly influence the risk of tooth sensitivity (P>.05). No significant differences were found between groups regarding color change (P>.05)., Conclusions: The use of an extended bleaching tray design increases the risk of gingival irritation and the intensity of tooth sensitivity. Therefore, the nonextended tray is recommended to minimize adverse reactions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardioneuroablation (CNA) represents a promising therapy for recurrent vasovagal syncope (VVS), extrinsically driven atrioventricular block (AVB) and sinus node dysfunction (SND). However, effectiveness in patients aged 50 and above is not well-established. In this prospective study of patients referred for CNA, we compared syncope and pacemaker implantation free survival, heart rate (HR) variability (HRV) and quality of life between two age groups: group A (< 50 years) and B (≥ 50 years). A total of 50 patients were included (17 Group A and 33 Group B). The etiologies comprised VVS (56%), AVB (22%), and SND (22%). After a median follow-up of 17.0 (12.5-26.0) months, there were no differences of the combined endpoint of syncope or pacemaker implantation free-survival between groups (29.4.% vs. 21.2%; p-log-rank = 0.736). 84% of the entire cohort remained free from syncope, with a better but not significant syncope free survival in the older group (23.5% vs. 12.1%; p-log rank = 0.486). There were no differences in pacemaker implantation rate (A 5.9% vs. B 17.6%; p log-rank = 0.658). Notably, older patients had lower HR values post-procedure compared to younger patients (68.9 ± 13.3 vs. 80.4 ± 16.3 bpm; p = 0.012). Both groups exhibited a decrease in HRV parameters and an improvement in quality of life. In conclusion, CNA has comparable clinical benefits for patients aged 50 and above in terms of syncope or pacemaker implantation free survival and HRV reduction when compared to younger patients., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Catechol- O -methyltransferase inhibitors (iCOMT), such as entacapone, have been successfully employed to treat tremor-related symptoms of Parkinson's disease. However, iCOMT has been associated with a short half-life and poor oral bioavailability. Nanobased drug delivery systems have often been used to overcome this type of setbacks. Therefore, entacapone was encapsulated in PEGylated poly(lactic- co -glycolic acid) (PLGA)-based nanoparticles (NPs) via a nanoprecipitation process, as well as in PEGylated nanostructured lipid carriers (NLCs) using a solvent emulsification/evaporation method. Both nanoformulations presented sub-200 nm populations, with zeta-potential (ZP) values close to -30 mV, and showed stability at different pHs, while maintaining their physicochemical properties mostly intact, presenting only a change in their superficial charge (ZP values), indicating their interaction. Both nanoformulations presented interaction with mucins, which anticipates good permeation and bioavailability for oral and topical administration. No cytotoxic effects were observed for lyophilized PLGA NPs encapsulating entacapone, in which 2-hydroxypropyl-ß-cyclodextrin (HPβCD) was used as a cryoprotectant at 3% concentration (HP-PLGA@Ent), in human hepatocellular carcinoma (HepG2), human neuroblastoma (SH-SY5Y), or human epithelial colorectal adenocarcinoma (Caco-2) cell lines. Conversely, NLCs encapsulating entacapone (W-NLCs@Ent) presented cytotoxic effects on the HepG2 cell line, likely due to intracellular lipid accumulation or storage. Both nanoformulations maintained a COMT inhibition effect in HepG2 cells, using 3-BTD as the COMT probe. An increase of entacapone permeability in both monolayer and coculture models (Caco-2 and Caco-2/HT29-MTX, respectively) was observed for the developed nanoformulations. Overall, this work shows that encapsulated entacapone in different nanocarriers could be a stimulating alternative to solve entacapone setbacks, since they improve its physicochemical properties and permeability while still maintaining the COMT inhibitory activity.

Objective: To describe the design and development of prevANS, a personalized online intervention for the universal prevention of anxiety disorders based on a predictive risk algorithm. A user-centered approach was followed, considering the feedback of potential users and mental health professionals., Methods: The study had three phases: (a) designing the intervention based on existing scientific literature; (b) piloting and evaluating the beta version involving potential users and health professionals; and (c) refining the intervention based on participants' suggestions. This iterative process aimed to refine the prevANS intervention before testing in a randomized controlled trial., Results: The prevANS intervention provides personalized anxiety risk reports and components tailored to individuals' needs. Participants at low risk receive psychoeducation had access to a set of tools enhance protective factors. Moderate/high-risk individuals also receive cognitive-behavioral training. Both groups have access to a reward system and forum. Results from the design evaluation indicate that the prevANS interface is attractive and user-friendly and the psychoeducational materials helpful and engaging. The cognitive-behavioral training module received positive feedback. Participants suggested changes related to usability, content clarity, attractiveness, and engagement, which were implemented afterwards., Conclusions: This article describes the development of a personalized intervention for preventing anxiety disorders using a validated risk prediction algorithm. The prevANS intervention was designed based on current scientific literature by a team of experts employing a user-centered approach. Research on the effectiveness of information and communication technologies in mental health prevention interventions considering user needs and preferences is warranted., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Introduction: Carotid sinus syndrome (CSS), characterized by exaggerated vagal responses leading to asystolic pauses with carotid sinus massage (CSM), often necessitates pacemaker implantation. This study investigates cardioneuroablation (CNA) as an alternative strategy for CSS., Methods: Prospective study of consecutive patients referred for CNA due to CSS. All patients underwent CSM, atropine test and 24-h Holter monitoring before the procedure and at 6 months. The primary objective was the absence of any cardioinhibitory response to CSM following CNA. Secondary objectives included the combined endpoint of syncope and presyncope-free survival, pacemaker-free survival, differences in heart rate variation (HRV), as well as differences in the pre- and postprocedure atropine tests and in the SF-36 quality-of-life questionnaire., Results: A total of 13 consecutive patients (84.6% male, mean age 63.8 ± 12.3 years) were included. CSM revealed a symptomatic asystolic pause in all patients before CNA (7.3 [5.6-10.5] s). After the procedure, all the patients had a negative CSM, and only one patient (7.7%) had a positive CSM at 6 months. After a median follow-up of 11.2 (10.6-16.3) months, syncope or presyncope-free survival was 84.6%, and none required pacemaker implantation. There was an improvement in the energy and health change items in the SF-36 questionnaire. There was a reduction in HR increase in the atropine test at 6 months (pre-CNA: 66% [52-84] vs. post-CNA 26.0% (19.8-29.3]; p = .008) and in HRV parameters., Conclusions: In this proof-of-efficacy study, performed in patients affected by asystolic CSS, CNA was effective in reducing the rate of cardioinhibitory responses, suggesting a potential efficacy in also reducing syncopal recurrences. Controlled trials are warranted to corroborate clinical findings., (© 2024 Wiley Periodicals LLC.)

The relationship between sensory processing, executive function, and behavior in children with Attention Deficit/Hyperactivity Disorder (ADHD) is far from clear. The aim of this study was to examine the mediating role of executive function in the relationship between sensory processing and behavior in ADHD. Sixty-three children (51 boys), aged between 7 and 14 years participated in this study. Caregivers completed the Sensory Profile 2 (SP-2), the Behavior Rating Inventory of Executive Function 2 (BRIEF-2), and the Child Behavior Checklist (CBCL) to assess sensory processing, executive function, and behavior, respectively. Positive and significant associations were found between sensory processing, executive function, and behavioral problems. In addition, positive indirect effects between sensory processing and behavior were mediated by executive function. These findings add to other evidence on neurodevelopmental disorders, suggesting that sensory processing may be a foundational aspect related to executive function, which in turn affects behavior in ADHD.

Introduction SUV measurements from static brain [ 18 F]FDG PET acquisitions are a commonly used tool in preclinical research, providing a simple alternative for kinetic modelling, which requires complex and time-consuming dynamic acquisitions. However, SUV can be severely affected by the animal handling and preconditioning protocols, primarily by those that may induce changes in blood glucose levels (BGL). Here, we aimed at developing and investigating the feasibility of SUV-based approaches for a wide range of BGL far beyond normal values, and consequently, to develop and validate a new model to generate standardized and reproducible SUV measurements for any BGL. Material and methods We performed dynamic and static brain [ 18 F]FDG PET acquisitions in 52 male Sprague-Dawley rats sorted into control (n = 10), non-fasting (n = 14), insulin-induced hypoglycemia (n = 12) and glucagon-induced hyperglycemia (n = 16) groups. Brain [ 18 F]FDG PET images were cropped, aligned and co-registered to a standard template to calculate whole-brain and regional SUV. Cerebral Metabolic Rate of Glucose (CMRglc) was also estimated from 2-Tissue Compartment Model (2TCM) and Patlak plot for validation purposes. Results Our results showed that BGL=100±6 mg/dL can be considered a reproducible reference value for normoglycemia. Furthermore, we successfully established a 2nd-degree polynomial model (C 1 =0.66E-4, C 2 =-0.0408 and C 3 =7.298) relying exclusively on BGL measures at pre-[ 18 F]FDG injection time, that characterizes more precisely the relationship between SUV and BGL for a wide range of BGL values (from 10 to 338 mg/dL). We confirmed the ability of this model to generate corrected SUV estimations that are highly correlated to CMRglc estimations (R 2 = 0.54 2TCM CMRgluc and R 2 = 0.49 Patlak CMRgluc). Besides, slight regional differences in SUV were found in animals from extreme BGL groups, showing that [ 18 F]FDG uptake is mostly directed toward central regions of the brain when BGLs are significantly decreased. Conclusion Our study successfully established a non-linear model that relies exclusively on pre-scan BGL measurements to characterize the relationship between [ 18 F]FDG SUV and BGL. The extensive validation confirmed its ability to generate SUV-based surrogates of CMRglu along a wide range of BGL and it holds the potential to be adopted as a standard protocol by the preclinical neuroimaging community using brain [ 18 F]FDG PET imaging., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Previous studies determined that Pyk2 is involved in several diseases in which the symptomatology presents alterations in energy balance. However, its role in obesity is poorly understood. To evaluate the metabolic role of the Pyk2 gene ( PTK2B ) in children and adolescents with obesity we measured its mRNA expression levels in peripheral blood mononuclear cells. For that we performed a cross-sectional study involving 130 Caucasian subjects that was divided into two groups according to BMI. Data showed increased PTK2B mRNA expression in children and adolescents with obesity. Interestingly, a positive correlation has been found between the levels of PTK2B with weight, BMI, BMI Z score, fat mass, waist circumference, waist to height ratio, diastolic blood pressure, and leptin. In addition, it is indicated that high levels of PTK2B gene expression might be a predictor of obesity development. This work provides important insights into the previously undescribed role of Pyk2 in obesity., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Two of 11 children with acute hepatitis of unknown origin were found to have rat hepatitis E virus infection. This infection should be considered in the differential diagnosis of children with acute hepatitis of unknown origin., Competing Interests: Declaration of Competing Interest This work was supported by the Andalusian General Secretariat for Research, Development, and Innovation in Health (PI-0287-2019), the Spanish Ministry of Health (RD12/0017/0012), co-financed by European Regional Development Fund (ERDF), and the Carlos III Health Institute (Research Project grant numbers: PI21/00  793 and PI22/01  098). Projects “PI21/00  793” and “PI22/01  098” were funded by Carlos III Health Institute (ISCIII) and co-funded by the European Union. LRM is the recipient of a “INVESTIGO” research program grant funded by the European Union NextGenerationEU Plan. MCJ is the recipient of a PFIS predoctoral grant (FI22/00  180) from the Carlos III Health Institute and co-funded by the European Union. ARJ is supported by a contract from the Spanish Junta de Andalucía (Nicolas Monardes program: C1-0001-2023). JCG is supported by the CIBERINFEC (CB21/13/00  083), Carlos III Health Institute, Spanish Ministry of Science, and NextGenerationEU. The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: There has been a rise in endometrial cancer (EC) incidence leading to increased mortality. To counter this trend, improving the stratification of post-surgery recurrence risk and anticipating disease relapse and treatment resistance is essential. Liquid biopsy analyses offer a promising tool for these clinical challenges, though the best strategy for applying them in EC must be defined. This study was designed to determine the value of cfDNA/ctDNA monitoring in improving the clinical management of patients with localized and recurrent disease., Methods: Plasma samples and uterine aspirates (UA) from 198 EC patients were collected at surgery and over time. The genetic landscape of UAs was characterized using targeted sequencing. Total cfDNA was analyzed for ctDNA presence based on the UA mutational profile., Results: High cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for DFS (p-value < 0.0001; HR = 9.25) and DSS (p-value < 0.0001; HR = 11.20). This remained clinically significant when stratifying tumors by histopathological risk factors. Of note, cfDNA/ctDNA analyses discriminated patients with early post-surgery relapse and the ctDNA kinetics served to identify patients undergoing relapse before any clinical evidence emerged., Conclusions: This is the most comprehensive study on cfDNA/ctDNA characterization in EC, demonstrating its value in improving risk stratification and anticipating disease relapse in patients with localized disease. CtDNA kinetics assessment complements current strategies to monitor the disease evolution and the treatment response. Therefore, implementing cfDNA/ctDNA monitoring in clinical routines offers a unique opportunity to improve EC management., Translational Relevance: The study demonstrates that high levels of cfDNA and detectable ctDNA at baseline are strong indicators of poor prognosis. This enables more accurate risk stratification beyond traditional histopathological factors, allowing clinicians to identify high-risk patients who may benefit from more aggressive treatment and closer monitoring. Moreover, longitudinal analysis of cfDNA/ctDNA can detect disease recurrence months before clinical symptoms or imaging evidence appear. This early warning system offers a significant advantage in clinical practice, providing a window of opportunity for early intervention and potentially improving patient outcomes., (© 2024. The Author(s).)

Ophthalmic tacrolimus compounded formulations are usually made from the commercial intravenous presentation, which contains ethanol as a solubilizer due to the low solubility of tacrolimus. The use of cyclodextrins is presented as an alternative to ethanol, an ocular irritant excipient, to avoid its long-term irritant effects. Open-label, sequential, prospective study to compare effectiveness, safety, and adherence of a new formulation of 0.015% tacrolimus with cyclodextrins (TCD) versus 0.03% tacrolimus with ethanol (TE). The ocular evaluation was assessed by ocular signs, corneal staining, subjective questionnaires as Visual Function Questionnaire (VFQ-25) and Visual Analogue Scale (VAS) of symptoms, lacrimal stability, ocular redness, and intraocular pressure. Compliance was assessed by VAS of adherence and empirically (difference between theoretical and actual consumption). Clinical ocular signs and corneal staining score remained stable for most patients 3 months after switching formulations. The TCD formulation did not modify the tear stability and intraocular pressure of the treated patients compared to the TE formulation. TCD eye drops significantly decreased the subjective pain values on VFQ-25 scale and burning sensation on the VAS symptom scale in comparison to TE formulation after 3 months after the change to TCD formulation. The novel tacrolimus in cyclodextrins formulation is a promising alternative for treating inflammatory ocular pathologies refractory to first-line treatments.

Introduction: Compared with the operating room, tracheal intubations in the intensive care unit (ICU) are associated with worsened glottic view, decreased first-time success rate and increase in the technical difficulty of intubation and incidence of complications. Videolaryngoscopes (VLs) have been proposed to improve airway management, and while recent studies have confirmed that VLs improve intubation conditions in this patient population, there remains a lack of clarity regarding the selection between a standard Macintosh blade or a hyperangulated one, to determine which yields the best outcomes. The purpose of this study was to compare successful intubation on the first attempt with the Macintosh VL versus the hyperangulated VL during tracheal intubation in ICU patients. We hypothesise that tracheal intubation using the hyperangulated VL will improve the frequency of successful intubation on the first attempt., Methods and Analysis: The INtubation VIdeolaryngoscopy BLADE-ICU trial is a prospective, multicentre, open-label, interventional, randomised, controlled superiority study conducted in 29 ICUs in Spain. Patients will be randomly assigned in a 1:1 ratio to undergo intubation using a Macintosh VL (control group) or a hyperangulated VL (experimental group) for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcomes include the time to intubation, attempts for successful intubation, laryngoscopic vision assessed with the modified Cormack-Lehane scale, the need for adjuvant airway devices for intubation, difficulty assessed by the anaesthesiologist and complications during tracheal intubation. Enrolment began on 1 May 2024 and is expected to be completed in 2025., Ethics and Dissemination: The study protocol was approved on 29 February 2024, by the Ethics Committee of Galicia (CEImG, code No. 2024-031).The results will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT06322719., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Uveitis is a group of inflammatory ocular pathologies. Endotoxin-Induced Uveitis (EIU) model represent a well-known model induced by administration of Lipopolysaccharide (LPS). The aim is to characterize two models of EIU through two routes of administration with novel noninvasive imaging techniques. 29 rats underwent Intraocular Pressure (IOP) measurements, Optical Coherence Tomography (OCT), proteomic analysis, and Positron Emission Tomography and Computed Tomography (PET/CT). Groups included healthy controls (C), BSS administered controls (Ci), systemically induced EIU with LPS (LPSs), and intravitreally induced EIU with LPS (LPSi) for IOP, OCT, and proteomic studies. For 18 F-FDG PET/CT study, animals were divided into FDG-C, FDG-LPSs and FDG-LPSi groups and scanned using a preclinical PET/CT system. LPSi animals exhibited higher IOP post-induction compared to C and LPSs groups. LPSi showed increased cellular infiltrate, fibrotic membranes, and iris inflammation. Proinflammatory proteins were more expressed in EIU models, especially LPSi. PET/CT indicated higher eye uptake in induced models compared to FDG-C. FDG-LPSi showed higher eye uptake than FDG-LPSs but systemic uptake was higher in FDG-LPSs due to generalized inflammation. OCT is valuable for anterior segment assessment in experimental models. 18 F-FDG PET/CT shows promise as a noninvasive biomarker for ocular inflammatory diseases. Intravitreal induction leads to higher ocular inflammation. These findings offer insights for future inflammatory disease research and drug studies., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Molecular dynamics (MD) simulations are currently an indispensable tool to understand both the dynamic and nanoscale organization of cell membrane models. A large number of quantitative parameters can be extracted from these simulations, but their reliability is determined by the quality of the employed force field and the simulation parameters. Much of the work on parametrizing and optimizing force fields for biomembrane modeling has been focused on homogeneous bilayers with a single phospholipid type. However, these may not perform effectively or could even be unsuitable for lipid mixtures commonly employed in membrane models. This work aims to fill this gap by comparing MD simulation results of several bacterial membrane models using different force fields and simulation parameters, namely, CHARMM36, Slipids, and GROMOS-CKP. Furthermore, the hydrogen isotope exchange (HIE) method, combined with GROMOS-CKP (GROMOS-H2Q), was also tested to check for the impact of this acceleration strategy on the performance of the force field. A common set of simulation parameters was employed for all of the force fields in addition to those corresponding to the original parametrization of each of them. Furthermore, new experimental order parameter values determined from NMR of several lipid mixtures are also reported to compare them with those determined from MD simulations. Our results reveal that most of the calculated physical properties of bacterial membrane models from MD simulations are substantially force field and lipid composition dependent. Some lipid mixtures exhibit nearly ideal behaviors, while the interaction of different lipid types in other mixtures is highly synergistic. None of the employed force fields seem to be clearly superior to the other three, each having its own strengths and weaknesses. Slipids are notably effective at replicating the order parameters for all acyl chains, including those in lipid mixtures, but they offer the least accurate results for headgroup parameters. Conversely, CHARMM provides almost perfect estimates for the order parameters of the headgroups but tends to overestimate those of the lipid tails. The GROMOS parametrizations deliver reasonable order parameters for entire lipid molecules, including multicomponent bilayers, although they do not reach the accuracy of Slipids for tails or CHARMM for headgroups. Importantly, GROMOS-H2Q stands out for its computational efficiency, being at least 3 times faster than GROMOS, which is already faster than both CHARMM and Slipids. In turn, GROMOS-H2Q yields much higher compressibilities compared to all other parametrizations.

Background: This article aspires to show that pterygoid implants are a magnificent and viable alternative to other posterior implants of the maxilla, especially in cases of atrophy., Material and Methods: This study is based on a retrospective analysis of pterygoid implant data from 2003 to 2023, recollecting the following variables: year of placement, location, shape of the implant, diameter of the implant, length of the implant, torque of the implant, whether or not it was post-extraction, whether or not there was immediate loading, whether or not smoking was present (smoking habit), the brand of the implant and the success/survival or failure/non survival of the implant., Results: The total of 178 pterygoid implants placed in the 113 patients eligible for the study was analysed by subgroups, with percentage of global success of 98.3% (3 failures)., Conclusions: Pterygoid implants offer biomechanical and success/survival characteristics similar or superior to the so-called conventional implants and avoid a series of surgical and prosthodontic procedures more difficult than the ones required by other implants in many occasions.

Chronic respiratory diseases (CRD) are responsible for more than four million deaths worldwide and have become especially prevalent in developed countries. Although the current therapies help manage daily symptoms and improve patients' quality of life, there is a major need to prevent exacerbations triggered mainly by respiratory infections. Therefore, CRD patients are a prime target for vaccination against infectious agents. In the present manuscript we review the state of the art of available vaccines specifically indicated in patients with CRDs. In addition to pneumococcus, influenza, pertussis, and SARS-CoV-2 vaccines, recently added immunization options like vaccines and monoclonal antibodies against respiratory syncytial virus, are particularly interesting in CRD patients. As new products reach the market, health authorities must be agile in updating immunization recommendations and in the programming of the vaccination of vulnerable populations such as patients with CRDs. Organizational and educational strategies might prove useful to increase vaccine uptake by CRD patients., (Copyright © 2024 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: The objective of this study was to develop a new website in Spanish on oral health and dental care for use by the relatives/caregivers of individuals with Down syndrome, with the aim of incorporating the strengths and avoids the deficiencies of existing websites., Methods: A freely accessible website was developed with dental content, whose access criteria included the age of the individual undergoing the consultation and the area of interest (tongue or teeth disease, oral functionality, oral hygiene, and dental visits). The definitive version of the website was analyzed by five external examiners, applying the DISCERN criteria and the Questionnaire to Evaluate Health Web Sites According to European Criteria (QEEC). The website's traffic during the first year of activity was recorded., Results: The new website is known as "DentiDown", and its access domain is https://odontoloxia-accessible.org/dentidown/. On the home screen, the age group of interest to the user can be accessed. A dropdown menu then opens, listing the various options according to the area of interest. The oral hygiene section provides advice for improving toothbrushing efficacy through demonstration videos. With the DISCERN tool, an overall score of 4.75 ± 0.5 was achieved. With the QEEC, the external examiners' general opinion was highly favorable. The website received the seal of quality from the Accredited Medical Web (AMW). During the first year of activity, a total of 4536 visits from a total of 45 countries were recorded., Conclusion: A new Spanish website has been developed on oral health for use by the relatives/caregivers of individuals with Down syndrome. The website has been favorably evaluated by external experts and, to date, is the only one with these characteristics with the AMW seal of quality., (© 2024 The Authors. Special Care in Dentistry published by Special Care Dentistry Association and Wiley Periodicals LLC.)

The ability of 18 F-FDG positron emission tomography (PET) to track disease activity and treatment response in patients with Ankylosing Spondylitis (AS) or Psoriatic Arthritis (PsA) remains unclear. Here, we assessed whether 18 F-FDG uptake is a marker of disease activity and treatment response in AS or PsA, and explored the ability of 18 F-FDG to predict treatment response. Patients with AS (n = 16) or PsA (n = 8) who were scheduled to initiate treatment with biologics were recruited. Participants underwent a clinical evaluation and an 18 F-FDG scan prior to therapy initiation. Eleven participants underwent a follow-up 18 F-FDG scan 3 months post-treatment. Images were quantified using a composite measure that describes the inflammatory status of the patient. Clinically involved joints/entheses had higher 18 F-FDG uptake compared to unaffected areas (median difference > 0.6, p < 0.01). Among patients with AS, pre-treatment 18 F-FDG uptake was strongly associated with disease activity (r = 0.65, p = 0.006). Longitudinal 18 F-FDG scans demonstrated that decreases in uptake at 3 months were associated to clinical response (β ΔgSUVmax  > 8.5, p < 0.001). We found no significant association between pre-treatment 18 F-FDG uptake and subsequent clinical response. 18 F-FDG PET shows potential as a marker of disease activity in AS and PsA, allowing for monitorization of biological treatment efficacy in these patients., (© 2024. The Author(s).)

Statement of Problem: Diagnostic casts can incorporate different base designs and be manufactured using different vat-polymerization technologies. However, the influence of the interrelation between the base design and the 3D printing technology on the casts' final accuracy remains unclear., Purpose: The purpose of this in vitro study was to assess the influence of different base designs of 3D printed casts on the accuracy of 2 vat-polymerization technologies., Material and Methods: A digital maxillary cast was obtained and used to generate 3 different base designs: solid (S group), honeycombed (HC group), and hollow (H group). The HC and H groups were subdivided based on the wall thickness of the cast design, resulting in 2 subgroups with thicknesses of 1 mm (HC1 and H1) and 2 mm (HC2 and H2) (N=100, n=10). Eleven reference cubes were added to each specimen for subsequent measurements. Specimens were manufactured by using 2 vat-polymerization 3D printers: Nextdent 5100 (ND group) and Sonic Mini 4K (SM4K group) and a resin material suitable for both 3D printers (Nextdent Model 2.0). A coordinate measuring machine quantified the linear and 3-dimensional discrepancies between the digital cast and each reference specimen. Trueness was defined as the average absolute dimensional discrepancy between the virtual cast and the specimens produced through additive manufacturing (AM), while precision was delineated as the standard deviation in dimensional discrepancies between the digital cast and the AM specimens. The data were analyzed using the Kruskal-Wallis and Mann-Whitney U pairwise comparison tests (α=.05)., Results: For the NextDent group the trueness ranged from 21.83 µm to 28.35 µm, and the precision ranged from 17.82 µm to 37.70 µm. For the Phrozen group, the trueness ranged from 45.15 µm to 64.51 µm, and the precision ranged from 33.51 µm to 48.92 µm. The Kruskal-Wallis test showed significant differences on the x-, y-, and z-axes and in the 3D discrepancy (all P<.001). On the x-axis, the Mann-Whitney U test showed significant differences for the Phrozen group between the H-2 and H-1 groups (P=.001), H-2 and S groups (P<.001), and HC-2 and S groups (P=.012). On the y-axis, significant differences were found in the Phrozen group between the H-2 and H-1 groups (P=.001), the H-2 and S, H-1 and HC-1, and HC-1 and S groups (P<.001), the H-1 and HC-2 groups (P=.007), and the HC-2 and S groups (P=.009). The NextDent group exhibited significant differences, particularly among the HC-1 and H-2 groups (P=.004), H-1 (P=.020), and HC-2 (P=.001) groups; and on the z-axis significant differences were found in the Phrozen group between the H-2 and H-1 and S groups and the HC-2 group and H-1 and S groups (both P<.001). In the NextDent group, significant differences were found between the H-2 and HC-2 (P=.047) and HC-1 (P=.028) groups. For the 3D discrepancy analysis, significant differences were found in the Phrozen group between the H-2 and H-1 and S groups (P<.001), the H-1 and HC-2 groups (P=.001), the S and HC-1 and HC-2 groups (P<.001), and the H-1 and HC-1 groups (P=.002). In the NextDent group, significant differences were observed between the H-2 and HC-1 groups (P=.012)., Conclusions: The accuracy of digital casts depends on the manufacturing trinomial and base design of the casts. The honeycomb and hollow based designs provided the highest accuracy in the NextDent and Phrozen groups respectively for the material polymer tested. All specimens fell in the clinically acceptable range., (Copyright © 2024 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Background: Galicia (Spain) was one of the first regions worldwide to incorporate nirsevimab for universal respiratory syncytial virus (RSV) prophylaxis in infants into its immunisation programme. The NIRSE-GAL longitudinal population-based study aimed to assess nirsevimab effectiveness in preventing hospitalisations (ie, admittance to hospital)., Methods: The 2023-24 immunisation campaign with nirsevimab in Galicia began on Sept 25, 2023, and concluded on March 31, 2024. The campaign targeted three groups: infants born during the campaign (seasonal group), infants younger than 6 months at the start of the campaign (catch-up group), and infants aged 6-24 months with high-risk factors at the start of the campaign (high-risk group). Infants in the seasonal group were offered immunisation on the first day of life before discharge from hospital. Infants in the catch-up and high-risk groups received electronic appointments to attend a public hospital or health-care centre for nirsevimab administration. For this interim analysis, we used data collected from Sept 25 to Dec 31, 2023, from children born up to Dec 15, 2023. Data were retrieved from public health registries. Nirsevimab effectiveness in preventing RSV-associated lower respiratory tract infection (LRTI) hospitalisations; severe RSV-related LRTI requiring intensive care unit admission, mechanical ventilation, or oxygen support; all-cause LRTI hospitalisations; and all-cause hospitalisations was estimated using adjusted Poisson regression models. Data from five past RSV seasons (2016-17, 2017-18, 2018-19, 2019-20, and 2022-23), excluding the COVID-19 pandemic period, were used to estimate the number of RSV-related LRTI hospitalisations averted along with its IQR. The number needed to immunise to avoid one case in the 2023-24 season was then estimated from the averted cases. Nirsevimab safety was routinely monitored. The NIRSE-GAL study protocol was registered on ClinicalTrials.gov (NCT06180993), and follow-up of participants is ongoing., Findings: 9408 (91·7%) of 10 259 eligible infants in the seasonal and catch-up groups received nirsevimab, including 6220 (89·9%) of 6919 in the catch-up group and 3188 (95·4%) of 3340 in the seasonal group. 360 in the high-risk group were offered nirsevimab, 348 (97%) of whom received it. Only infants in the seasonal and catch-up groups were included in analyses to estimate nirsevimab effectiveness and impact because there were too few events in the high-risk group. In the catch-up and seasonal groups combined, 30 (0·3%) of 9408 infants who received nirsevimab and 16 (1·9%) of 851 who did not receive nirsevimab were hospitalised for RSV-related LRTI, corresponding to an effectiveness of 82·0% (95% CI 65·6-90·2). Effectiveness was 86·9% (69·1-94·2) against severe RSV-related LRTI requiring oxygen support, 69·2% (55·9-78·0) against all-cause LRTI hospitalisations, and 66·2% (56·0-73·7) against all-cause hospitalisations. Nirsevimab effectiveness against other endpoints of severe RSV-related LRTI could not be estimated because of too few events. RSV-related LRTI hospitalisations were reduced by 89·8% (IQR 87·5-90·3), and the number needed to immunise to avoid one RSV-related LRTI hospitalisation was 25 (IQR 24-32). No severe adverse events related to nirsevimab were registered., Interpretation: Nirsevimab substantially reduced infant hospitalisations for RSV-associated LRTI, severe RSV-associated LRTI requiring oxygen, and all-cause LRTI when given in real-world conditions. These findings offer policy makers and health authorities robust, real-world, population-based evidence to guide the development of strategies for RSV prevention., Funding: Sanofi and AstraZeneca., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests FM-T reports having acted as principal investigator in randomised controlled trials for Ablynx, Abbott, Seqirus, Sanofi Pasteur, Cubist, Wyeth, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis, and GSK, with honoraria paid to his institution and relationships with GSK Vaccines, Pfizer, Sanofi Pasteur, Janssen Pharmaceuticals, MSD, and Seqirus that include consulting or advisory roles. RK, JJ, and LP-A are Sanofi employees and hold shares or stock options in the company. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects.

Computer-aided design and computer-aided manufacturing (CAD-CAM) technologies have been integrated into the dental digital workflow. However, pretreatment virtual veneer preparations and the digital design and manufacturing of guided preparation and cementation templates has not yet been incorporated into the clinical routine. This article presents a novel protocol for digitally guided veneer rehabilitation by following the esthetic integration area concept, facilitating precise control over tooth structure removal and obviating the need for interim restorations., (Copyright © 2024 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Aims: This study's main objective was to analyze the discrepancy between the dental medication record (DMR) and the physician-prescribed active medications recorded in the medical medication record (MMR)., Methods: The study group consisted of 100 adults who attended the University Dental Clinic (Santiago de Compostela, Spain) requesting dental care. A dental history was created for all participants that included the DMR. The MMR were compiled from their electronic medical records., Results: About 80% of the patients consumed at least one drug (94.2% of those >65 years) and 19% took more than five drugs (26.4% of those > 65 years). In total, 54% of the patients had some discrepancy between the medications recorded in the DMR and those in the MMR (48.4% for those ≤65 years and 64.7% for those >65 years). The rate of participants who omitted some drugs was higher for those >65 years. The drugs most omitted from the DMR were analgesics/opioids, antihypertensives and anxiolytics/hypnotics/sedatives., Conclusions: It is imperative to access the MMR of patients requesting dental care because a significant number of medications are not reflected in their DMR. These discrepancies may be particularly common and relevant in elderly patients, in whom multimorbidity and polypharmacy are more frequent., (© 2024 Special Care Dentistry Association and Wiley Periodicals LLC.)

Background: In 1973, Saunders T. Frank described the diagonal earlobe crease (DELC) as a potential marker of cardiovascular disease. However, this anatomical finding is not routinely examined. The aim of this study was to assess the presence of this crease in the general population attending a dental setting and describe its anatomical variations to be able to categorize it as a physical sign., Methodology: A study group of 1050 white adults were selected, as participants in the framework of the "A Estrada Study of Glycation and Inflammation" (AEGIS), a cross-sectional, population-based descriptive study of a representative sample of the general adult population of the municipality of A Estrada (Pontevedra, Spain). Each participant's age, sex, and preferred head position when sleeping were recorded. Both earlobes were visually inspected and the anatomical variables of the crease were recorded (unilateral or bilateral, length, depth, and presence of secondary creases). The relationship between the study variables was analyzed using the chi-squared test, Student's t-test, the analysis of variance (ANOVA), and the nonparametric tests of Mann-Whitney and Kruskal-Wallis., Results: The DELC was observed in 65.2% of the participants. In 71.5% of the cases, the sign was complete (occupying the space from the tragus to the posterior edge of the earlobe); in 56.9% of the cases, the sign was bilateral; in 45.1% of the cases it was deep; and in the 43.6% of the cases, accessory creases were identified. Neither sex nor the habitual head position when sleeping were related to the prevalence or characteristics of the DELC. The prevalence, extent and depth of Frank's sign increased significantly with age (p < .001)., Conclusion: The prevalence of the DELC increases significantly with age, and its morphological characteristics are accentuated. This finding, therefore, gains special relevance as a marker of potential cardiovascular disease when observed in young adults., (© 2024 The Authors. Special Care in Dentistry published by Special Care Dentistry Association and Wiley Periodicals LLC.)

Background: Although atrial fibrosis has a relevant impact on ablation success rate, experimental studies have reported that extensive fibrosis may be accompanied by a reduced burden secondary to a prominent depression of atrial excitability., Objectives: We aimed to identify clinical and echocardiographic factors associated with extensive left atrial myopathy (ELAM), to analyze the predictive ability of established scores (AF score, APPLE, and DR-FLASH) and assess outcomes in terms of AF recurrence, left atrial flutter, and post-procedural heart failure admissions., Methods: A total of 950 consecutive patients undergoing the first AF ablation were included. A 3D electroanatomical mapping system (CARTO3, Biosense Webster) was created using a multipolar mapping catheter (PentaRay, Biosense Webster). ELAM was defined as ≥ 50% low voltage area. A subanalysis with four groups was also created (< 10%; 10-20%; 10-20%; and > 30%). Logistic regressions, Cox proportional hazards models, and log-rank test were used to test the predictors independently associated with the presence of ELAM and AF recurrence. The model was prospectively validated in a cohort of 150 patients obtaining an excellent ability for prediction AUC 0.90 (CI 95% 0.84-0.96)., Results: Overall, 78 (8.42%) presented ELAM. Age, female sex, persistent AF, first-degree AV block, and E/e' were significant predictors. The model incorporating these factors outperformed the existing scores (AUC = 0.87). During a mean follow-up of 20 months (IQR 9 to 36), patients with ELAM presented a higher rate of AF recurrence (42.02% vs 26.01%, p = 0.030), left atrial flutter (26.03% vs 8.02%, p < 0.001), and post-procedural heart failure admissions (12.01% vs 0.61%, p < 0.001) than non-ELAM patients., Conclusions: This study reveals the incidence and clinical factors associated with ELAM in AF, highlighting age, female, persistent AF, first-degree AV block, and E/e'. Importantly, the presence of ELAM is associated with poorer outcomes in terms of recurrence and HF admission., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Diffusion cells play a crucial role in the pharmaceutical and cosmetic fields by assessing the release and permeation of active pharmaceutical ingredients across membranes. However, commercially available glass-based devices, such as Franz diffusion cells, are expensive and fragile. The emergence of three-dimensional (3D) printing technology enables the creation of diffusion cells with cost-effective polymeric materials and resins, offering exceptional precision and custom geometries. Nonetheless, there are challenges associated with interactions between 3D printing materials and drug molecules. This work aimed to develop inert coatings for 3D-printed diffusion models. Diffusion devices were designed and 3D-printed with a stereolithography (SLA) 3D printer, and different coatings were applied. Then, two model drugs were used to evaluate drug retention by coated devices. Among the tested coatings, one of them showed great potential in preventing drug retention and was selected for subsequent experiments with different drugs and conditions. Finally, voriconazole eyedrops were used to confirm the viability of 3D-printed Franz diffusion cells as a drug release diffusion model. The favourable results obtained with the coating promote the use of 3D printing as a cost-effective manufacturing technology, capable of producing diffusion cells tailored to specific study requirements., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Despite the high success rates of dental implants, peri-implantitis is currently the most common complication in dental implantology. Peri-implantitis has an inflammatory nature, it is associated with the accumulation of plaque in the peri-implant tissues, and its evolution can be progressive depending on various factors, comorbidities, and poor oral health. Prophylaxis and different treatment methods have been widely discussed in recent decades, and surgical and non-surgical techniques present both advantages and disadvantages. In this work, a literature review of different studies on the application of adjuvant treatments, such as local and systemic antibiotics and antiseptic treatments, was conducted. Positive outcomes have been found in the short (up to one year after treatment) and long term (up to ten years after treatment) with combined therapies. However, there is still a need to explore new therapies based on the use of advanced drug delivery systems for the effective treatment of peri-implantitis in the long term and without relapses. Hence, micro- and nanoparticles, implants, and injectable hydrogels, among others, should be considered in future peri-implantitis treatment with the aim of enhancing overall therapy outcomes.

Introduction: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management., Objectives: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression., Methods: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables., Results: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs)., Conclusions: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

This work attempted to clarify the interaction of cognition and pain sensitization during a paradigm of Temporal Summation of Second Pain (TSSP). We analyzed pain ratings and electroencephalographic (EEG) activity obtained from 21 healthy participants during the presentation of four experimental conditions that differed in the manipulation of attention to painful stimuli or working memory load (Attention to hand & TSSP; 0-back & TSSP (low cognitive load); 2-back & TSSP (high cognitive load); 2-back (without pain)). We found that the TSSP was reduced when the attention was diverted and the cognitive load increased, and this reduction was accompanied by higher midfrontal theta activity and lower posterior alpha and central beta activity. Although it is well established that TSSP is a phenomenon that occurs at the spinal level, here we show that it is also affected by supraspinal attentional mechanisms. Delivery of painful repeated stimuli did not affect the performance of the 2-back task but was associated with smaller amplitudes of attentional event-related potentials (ERPs) after standard stimuli (not the target). The study of brain activity during TSSP allowed to clarify the role of top-down attentional modulation in pain sensitization processes. Results contribute to a better understanding of cognitive dysfunction in pain conditions and reinforce the use of therapeutic strategies based on distracting attention away from pain., (© 2024 The Author(s). Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Background: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable., Methods: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study., Results: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11)., Conclusion: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented)., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. AEAY has received speaker/advisory board fees from Janssen, Abdi İbrahim Otsuka and Nobel, and has received investigator fees from Janssen. CBE received honoraria for conferences from Forum pour la formation médicale, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma, and Zeller in the past 3 years. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SHK has received research grants from Janssen and Dongwha. JGL has consulted/spoken on behalf of Saladax Biomedical. RMP has received speaker/consultation fees from Eisai, HLS Therapeutics, Jansen, Lundbeck, and Otsuka. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

The characterization of the time course of ibuprofen enantiomers can be useful in the selection of the most sensitive analyte in bioequivalence studies. Physiologically based pharmacokinetic (PBPK) modelling and simulation represents the most efficient methodology to virtually assess bioequivalence outcomes. In this work, we aim to develop and verify a PBPK model for ibuprofen enantiomers administered as a racemic mixture with different immediate release dosage forms to anticipate bioequivalence outcomes based on different particle size distributions. A PBPK model incorporating stereoselectivity and non-linearity in plasma protein binding and metabolism as well as R-to-S unidirectional inversion has been developed in Simcyp®. A dataset composed of 11 Phase I clinical trials with 54 scenarios (27 per enantiomer) and 14,452 observations (7129 for R-ibuprofen and 7323 for S-ibuprofen) was used. Prediction errors for AUC 0-t and C max for both enantiomers fell within the 0.8-1.25 range in 50/54 (93 %) and 42/54 (78 %) of scenarios, respectively. Outstanding model performance, with 10/10 (100 %) of C max and 9/10 (90 %) of AUC 0-t within the 0.9-1.1 range, was demonstrated for oral suspensions, which strongly supported its use for bioequivalence risk assessment. The deterministic bioequivalence risk assessment has revealed R-ibuprofen as the most sensitive analyte to detect differences in particle size distribution for oral suspensions containing 400 mg of racemic ibuprofen, suggesting that achiral bioanalytical methods would increase type II error and declare non-bioequivalence for formulations that are bioequivalent for the eutomer., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SH Kim has received research grants from Janssen and Dongwha. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Loop-mediated isothermal amplification, LAMP, is nowadays the most popular isothermal nucleic acid amplification technique, and as such, several commercial, ready-to-use master mixes have flourished. Unfortunately, independent studies to determine their performance are limited. The current study performed an independent evaluation of the existing ready-to-use commercial LAMP master mixes WarmStart ® LAMP Kit, LavaLAMP™ DNA Master Mix, Saphir Bst Turbo GreenMaster, OptiGene Fast Master Mix ISO-004, and SynLAMP Mix. To reduce bias, three different genes, namely ttr ( Salmonella spp.), rfbE ( E. coli O157), and hly ( Listeria monocytogenes ), were targeted. The comparison was based on amplification speed, performance with decreasing DNA concentrations, and the effect of five typical LAMP reaction additives (betaine, DMSO, pullulan, TMAC, and GuHCl). Significant differences were observed among the different master mixes. OptiGene provided the fastest amplification and showed less detrimental effects associated with the supplements evaluated. Out of the chemicals tested, pullulan provided the best results in terms of amplification speed. It is noteworthy that the different additives impacted the master mixes differently. Overall, the current study provides insights into the performance of commercial LAMP master mixes, which can be of value for the scientific community to better select appropriate reagents when developing new methods.

The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas., (© 2024. The Author(s).)

Introduction: Radium-223 dichloride (Ra-223) is recommended as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no visceral disease, after docetaxel failure, or in patients who are not candidates to receive it. In this study, we aimed to ambispectively analyze overall survival (OS) and prognostic features in mCRPC in patients receiving Ra-223 as per clinical routine practice and identify the most suitable treatment sequence., Patients and Methods: This study is observational, multicentric, and ambispective. Eligibility criteria included mCRPC patients treated with Ra-223, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, without visceral metastases, and no more than three cm involved lymph nodes., Results: A total of 145 patients were included; the median age was 73.97 years, and a Gleason score of more than or equal to 7 in 61 (48%) patients; 73 (81%) had previously received docetaxel. The most important benefit was reached by those patients who received Ra-223 in the second-line setting, with a median OS of 17 months (95% CI, 12-21), and by patients who received six cycles of treatment, with a median OS of 19 months (95% CI, 14-21). An alkaline phosphatase (ALP) decrease was also identified as a prognosis marker. When performing the multivariate analysis, the time to develop castration-resistant disease longer than 24 months was the most important prognostic factor to predict the evolution of the patients receiving Ra-223. Ra-223 was well tolerated, with thrombocytopenia, anemia, and diarrhea being the main adverse events., Conclusion: There is a benefit for those patients who received Ra-223 in the second-line setting, regardless of prior use of docetaxel. In addition, a survival benefit for patients presenting with a decline in ALP was observed., Competing Interests: UA-H — Consultant or advisory board: Advanced Accelerator Applications, Ipsen, Astra Zeneca, Merck, Pfizer, Astellas, Bayer, MSD, BMS; travel support: Ipsen, Bayer, Merck, Pfizer, GSK, Roche, Sanofi, Advanced Accelerator Applications; honoraria: Advanced Accelerator Applications, Ipsen, Astra Zeneca, Merck, Eisai, BMS, Rovi, Grünenthal Pharma, Leo Pharma an inmediate family member. JC-N — Consultant: Janssen, BMS; honoraria as speaker: Astellas, Bayer, Janssen. OF-C — Consultant or Advisory role: Astellas, BMS, Ipsen, Merck, Eisai; Honoraria as speaker: Novartis, BMS, Ipsen, Roche, Astellas, Bayer. NF-N — Advisory board: Pfizer; speaking honoraria: Ipsen, Roche, Bayer. AG-C — Scientific advice to Astellas, AstraZeneca, Bayer, Ipsen, Janssen; honoraria and consulting from Astellas, AstraZeneca, Bayer, Ipsen, Janssen; travel and lodging support from Astellas, AstraZeneca, Bayer, Ipsen, Janssen. ML — Consultant or AdvisoryRole: BMS, MSD, Takeda, Pfizer, Roche, Ipsen, Astra–Zéneca, Merck, Boehringer, Bayer, Novartis, AAA; speaking: Roche, Ipsen, MSD, Lilly, Astellas, Janssen, Novartis, Boehringer; grant or travel support: MSD, Ipsen, Roche, Janssen, Pfizer, Astellas, Pierre–Fabré; participation in clinical trials: Merck, Astellas, Pfizer, Ipsen, Roche, AstraZeneca, Mirati, PharmaMar. SM-B — Advisory role: Bayer, AstraZeneca, Astellas; Honoraria as speaker: Bayer, AstraZeneca, Novartis, Astellas, Janssen, Amgen. AM-D — Honoraria: Eisai, Grünenthal Pharma, Kyowa Kirin, Pharmamar, Merck, BMS, Roche, Ipsen; travel, accommodation, and congress: Pfizer, BMS, MSD, Eisai, Kyowa Kirin, Merck, Pharmamar, AstraZeneca, Lilly, Sanofi, Takeda, Astellas, Roche, Pierre Fabre; advisory board: Bayer, Eisai, Pierre Fabre, Pharmamar, Pfizer, Merck, Astellas, BMS. DP-F — Honoraria as consultant: Astellas, Bayer, Janssen; honoraria as speaker: Astellas, Bayer, Janssen, Ipsen; travel, accomodations and expenses: Astellas, Bayer, Janssen, Ipsen. JR-B — Travel, accommodations, and expenses: Merck, Pierre–Fabre, Sanofi, and Seagen; honoraria for educational activities: Ipsen; institutional research funding: Nouscom, Pfizer, and Roche. SV-E — Honoraria as consultant and advisory boards: Pfizer, Astellas, Janssen, MSD, Bayer, Roche, BMS, AztraZeneca, Ipsen, Organon and Merck; honoraria as speaker: Lilly, Astellas, Bayer, Roche, Ipsen, Janssen, Takeda, Merck, Organon and AstraZeneca; Travel grants: Pfizer, Roche, Ipsen and AstraZeneca. The remaining 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 Anido-Herranz, Fernandez-Calvo, Ruiz-Bañobre, Martinez-Breijo, Fernandez-Nuñez, Nogareda-Seoane, Garrido-Pumar, Casas-Nebra, Muñiz-Garcia, Portela-Pereira, Gomez-Caamaño, Perez-Fentes, Santome-Couto, Lázaro, Molina-Diaz, Medina-Colmenero and Vazquez-Estevez.)