Development of a new affinity maturation protocol for the construction of an internalizing anti-nucleolin antibody library.

Over the last decades, monoclonal antibodies have substantially improved the treatment of several conditions. The continuous search for novel therapeutic targets and improvements in antibody's structure, demands for a constant optimization of their development. In this regard, modulation of an antibody's affinity to its target has been largely explored and culminated in the discovery and optimization of a variety of molecules. It involves the creation of antibody libraries and selection against the target of interest. In this work, we aimed at developing a novel protocol to be used for the affinity maturation of an antibody previously developed by our group. An antibody library was constructed using an in vivo random mutagenesis approach that, to our knowledge, has not been used before for antibody development. Then, a cell-based phage display selection protocol was designed to allow the fast and simple screening of antibody clones capable of being internalized by target cells. Next generation sequencing coupled with computer analysis provided an extensive characterization of the created library and post-selection pool, that can be used as a guide for future antibody development. With a single selection step, an enrichment in the mutated antibody library, given by a decrease in almost 50% in sequence diversity, was achieved, and structural information useful in the study of the antibody-target interaction in the future was obtained.

Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.

This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.

A randomised, crossover trial exploring the patient perspective and effectiveness of biosimilar adalimumab transition: IBD reference and biosimilar adalimumab cross over study (iBaSS).

BACKGROUND: Patient satisfaction has been positively associated with adherence which is expected to impact outcomes. Although vital for successful implementation of biosimilar medicines, little is known about the patient perspective of transition. AIM: The aim of this study was to investigate clinical outcomes and patient experience of transitioning between reference adalimumab and a biosimilar (SB5). METHOD: iBaSS is a phase IV single-centre, prospective, randomised, single-blind, cross-over study in adult subjects with Crohn's disease. Participants, stable on adalimumab before consent, received 24 weeks of treatment with both reference adalimumab and SB5. The primary outcome was the proportion of patients maintaining baseline clinical status throughout each treatment period, with patients' perspective of disease control and treatment satisfaction assessed as secondary outcomes. RESULTS: A total of 112 participants, representative of the heterogeneous patient populations encountered in routine clinical practice, were enrolled. A similar proportion of participants maintained baseline clinical status through each treatment period: 81.8% with reference adalimumab and 79.5% with SB5. Patient reported outcomes (IBD-Control questionnaire (SB5: 15.5; reference adalimumab 15) and TSQM), adverse events and therapeutic drug monitoring remained consistent through both treatment periods, although a higher median injection pain VAS score was noted with SB5 (53/100 versus 6/100 with reference adalimumab). The number of switches undertaken in the study did not impact serum drug concentration or immunogenicity. CONCLUSION: This study, mimicking real world adalimumab transition, demonstrates that patients undertaking brand transition can be expected to have consistent clinical and satisfaction outcomes. CLINICAL TRIAL REGISTERED WITH EUDRACT: Number 2018-004967-30.

The first confirmed human case of rabies, Timor-Leste, 2024.

In March 2024, the first ever human case of rabies, following a dog bite, was detected in Timor-Leste. This paper briefly discusses the circumstances of transmission, clinical presentation, palliative care of the case and public health measures taken. Timor-Leste was previously considered rabies-free. Any person who is bitten or scratched by an animal that could potentially transmit rabies virus (especially dogs, bats, monkeys or cats) in Timor-Leste should be assessed for consideration of provision of rabies post-exposure prophylaxis.

Artificial intelligence as a prediction tool for orthognathic surgery assessment.

INTRODUCTION: An ideal orthodontic treatment involves qualitative and quantitative measurements of dental and skeletal components to evaluate patients' discrepancies, such as facial, occlusal, and functional characteristics. Deciding between orthodontics and orthognathic surgery remains challenging, especially in borderline patients. Advances in technology are aiding clinical decisions in orthodontics. The increasing availability of data and the era of big data enable the use of artificial intelligence to guide clinicians' diagnoses. This study aims to test the capacity of different machine learning (ML) models to predict whether orthognathic surgery or orthodontics treatment is required, using soft and hard tissue cephalometric values. METHODS: A total of 920 lateral radiographs from patients previously treated with either conventional orthodontics or in combination with orthognathic surgery were used, comprising n = 558 Class II and n = 362 Class III patients, respectively. Thirty-two measures were obtained from each cephalogram at the initial appointment. The subjects were randomly divided into training (n = 552), validation (n = 183), and test (n = 185) datasets, both as an entire sample and divided into Class II and Class III sub-groups. The extracted data were evaluated using 10 machine learning models and by a four-expert panel consisting of orthodontists (n = 2) and surgeons (n = 2). RESULTS: The combined prediction of 10 models showed top-ranked performance in the testing dataset for accuracy, F1-score, and AUC (entire sample: 0.707, 0.706, 0.791; Class II: 0.759, 0.758, 0.824; Class III: 0.822, 0.807, 0.89). CONCLUSIONS: The proposed combined 10 ML approach model accurately predicted the need for orthognathic surgery, showing better performance in Class III patients.

Cerebral Venous Thrombosis in Patients With Traumatic Brain Injury: Epidemiology and Outcome.

The natural history and epidemiological aspects of traumatic cerebral venous thrombosis (CVT) are not fully understood. Due to the concomitant occurrence with intracranial hemorrhages, guidelines for medical treatment have been highly controversial. In this study, our objective was to carry out an analysis description of the population and to conduct a literature review. A prospectively gathered radiology registry data of patients hospitalized at the tertiary hospital of Centro Hospitalar Universitário do São João, Porto, Portugal, between 2016 and 2021 was carried out. All patients with traumatic brain injury (TBI) and concomitant CVT were identified. CVT was confirmed by CT venogram. Demographic, clinical, and radiological data and their medical management were reported. In-hospital complications and treatment outcomes were compared between patients measured by the Glasgow Outcome Score Extended (GOSE) at discharge and GOSE at three months. There were 41 patients with traumatic CVT admitted to this study. The majority (45.2%) had a hyperdense signal near the lateral sinus at admission, and only 26.2% presented with skull fractures. Of this cohort, 95% had experienced lateral sinus thrombosis. Twenty-five patients (60%) had occlusive venous thrombosis. Venous infarct was the main complication following CVT. Thirty-two patients (78%) were anticoagulated after CVT and four developed complications. At the three-month follow-up after discharge, 28.2% had good recovery (GOSE > 6). This study revealed a higher incidence of CVT in severe TBI and a mild association with skull fractures. There is a higher incidence of CVT in the lateral sinus. Management was inconsistent, with no difference in outcome without or with anticoagulation. Larger, prospective cohort studies are required to better comprehend this condition and determine evidence-based guidelines.

Is three-piece maxillary segmentation surgery a stable procedure?

Objective: : The number of three-piece maxillary osteotomies has increased over the years; however, the literature remains controversial. The objective of this study was to evaluate the skeletal stability of this surgical modality compared with that of one-piece maxillary osteotomy. Methods: : This retrospective cohort study included 39 individuals who underwent Le Fort I maxillary osteotomies and were divided into two groups: group 1 (three pieces, n = 22) and group 2 (one piece, n = 17). Three cone-beam computed tomography scans from each patient (T1, pre-surgical; T2, post-surgical; and T3, follow-up) were used to evaluate the three-dimensional skeletal changes. Results: : The differences within groups were statistically significant only for group 1 in terms of surgical changes (T2-T1) with a mean difference in the canine region of 3.09 mm and the posterior region of 3.08 mm. No significant differences in surgical stability were identified between or within the groups. The mean values of the differences between groups were 0.05 mm (posterior region) and -0.39 mm (canine region). Conclusions: : Our findings suggest that one- and three-piece maxillary osteotomies result in similar post-surgical skeletal stability.

Balancing Act: Tubulin Glutamylation and Microtubule Dynamics in Toxoplasma gondii.

The success of the intracellular parasite Toxoplasma gondii in invading host cells relies on the apical complex, a specialized microtubule cytoskeleton structure associated with secretory organelles. The T. gondii genome encodes three isoforms of both α- and ß-tubulin, which undergo specific post-translational modifications (PTMs), altering the biochemical and biophysical proprieties of microtubules and modulating their interaction with associated proteins. Tubulin PTMs represent a powerful and evolutionarily conserved mechanism for generating tubulin diversity, forming a biochemical 'tubulin code' interpretable by microtubule-interacting factors. T. gondii exhibits various tubulin PTMs, including α-tubulin acetylation, α-tubulin detyrosination, Δ5α-tubulin, Δ2α-tubulin, α- and ß-tubulin polyglutamylation, and α- and ß-tubulin methylation. Tubulin glutamylation emerges as a key player in microtubule remodeling in Toxoplasma, regulating stability, dynamics, interaction with motor proteins, and severing enzymes. The balance of tubulin glutamylation is maintained through the coordinated action of polyglutamylases and deglutamylating enzymes. This work reviews and discusses current knowledge on T. gondii tubulin glutamylation. Through in silico identification of protein orthologs, we update the recognition of putative proteins related to glutamylation, contributing to a deeper understanding of its role in T. gondii biology.

2,4,5-Triaminopyrimidines as blue fluorescent probes for cell viability monitoring: synthesis, photophysical properties, and microscopy applications.

Monitoring cell viability is critical in cell biology, pathology, and drug discovery. Most cell viability assays are cell-destructive, time-consuming, expensive, and/or hazardous. Herein, we present a series of newly synthesized 2,4,5-triaminopyrimidine derivatives able to discriminate between live and dead cells. To our knowledge, these compounds are the first fluorescent nucleobase analogues (FNAs) with cell viability monitoring potential. These new fluorescent molecules are synthesized using highly efficient and cost-effective methods and feature unprecedented photophysical properties (longer absorption and emission wavelengths, environment-sensitive emission, and unprecedented brightness within FNAs). Using a live-dead Saccharomyces cerevisiae cell and theoretical assays, the fluorescent 2,4,5-triaminopyrimidine derivatives were found to specifically accumulate inside dead cells by interacting with dsDNA grooves, thus paving the way for the emergence of novel and safe fluorescent cell viability markers emitting in the blue region. As the majority of commercially available viability dyes emit in the green to red region of the visible spectrum, these novel markers might be useful to meet the needs of blue markers for co-staining combinations.

Dietary nitrate supplementation and cognitive health: the nitric oxide-dependent neurovascular coupling hypothesis.

Diet is currently recognized as a major modifiable agent of human health. In particular, dietary nitrate has been increasingly explored as a strategy to modulate different physiological mechanisms with demonstrated benefits in multiple organs, including gastrointestinal, cardiovascular, metabolic, and endocrine systems. An intriguing exception in this scenario has been the brain, for which the evidence of the nitrate benefits remains controversial. Upon consumption, nitrate can undergo sequential reduction reactions in vivo to produce nitric oxide (•NO), a ubiquitous paracrine messenger that supports multiple physiological events such as vasodilation and neuromodulation. In the brain, •NO plays a key role in neurovascular coupling, a fine process associated with the dynamic regulation of cerebral blood flow matching the metabolic needs of neurons and crucial for sustaining brain function. Neurovascular coupling dysregulation has been associated with neurodegeneration and cognitive dysfunction during different pathological conditions and aging. We discuss the potential biological action of nitrate on brain health, concerning the molecular mechanisms underpinning this association, particularly via modulation of •NO-dependent neurovascular coupling. The impact of nitrate supplementation on cognitive performance was scrutinized through preclinical and clinical data, suggesting that intervention length and the health condition of the participants are determinants of the outcome. Also, it stresses the need for multimodal quantitative studies relating cellular and mechanistic approaches to function coupled with behavior clinical outputs to understand whether a mechanistic relationship between dietary nitrate and cognitive health is operative in the brain. If proven, it supports the exciting hypothesis of cognitive enhancement via diet.

Changes in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failure.

STUDY QUESTION: Do the genetic determinants of idiopathic severe spermatogenic failure (SPGF) differ between generations? SUMMARY ANSWER: Our data support that the genetic component of idiopathic SPGF is impacted by dynamic changes in environmental exposures over decades. WHAT IS KNOWN ALREADY: The idiopathic form of SPGF has a multifactorial etiology wherein an interaction between genetic, epigenetic, and environmental factors leads to the disease onset and progression. At the genetic level, genome-wide association studies (GWASs) allow the analysis of millions of genetic variants across the genome in a hypothesis-free manner, as a valuable tool for identifying susceptibility risk loci. However, little is known about the specific role of non-genetic factors and their influence on the genetic determinants in this type of conditions. STUDY DESIGN, SIZE, DURATION: Case-control genetic association analyses were performed including a total of 912 SPGF cases and 1360 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants had European ancestry (Iberian and German). SPGF cases were diagnosed during the last decade either with idiopathic non-obstructive azoospermia (n = 547) or with idiopathic non-obstructive oligozoospermia (n = 365). Case-control genetic association analyses were performed by logistic regression models considering the generation as a covariate and by in silico functional characterization of the susceptibility genomic regions. MAIN RESULTS AND THE ROLE OF CHANCE: This analysis revealed 13 novel genetic association signals with SPGF, with eight of them being independent. The observed associations were mostly explained by the interaction between each lead variant and the age-group. Additionally, we established links between these loci and diverse non-genetic factors, such as toxic or dietary habits, respiratory disorders, and autoimmune diseases, which might potentially influence the genetic architecture of idiopathic SPGF. LARGE SCALE DATA: GWAS data are available from the authors upon reasonable request. LIMITATIONS, REASONS FOR CAUTION: Additional independent studies involving large cohorts in ethnically diverse populations are warranted to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Overall, this study proposes an innovative strategy to achieve a more precise understanding of conditions such as SPGF by considering the interactions between a variable exposome through different generations and genetic predisposition to complex diseases. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the "Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020)" (ref. PY20_00212, P20_00583), the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. PID2020-120157RB-I00 funded by MCIN/ AEI/10.13039/501100011033), and the 'Proyectos I+D+i del Programa Operativo FEDER 2020' (ref. B-CTS-584-UGR20). ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, is also partially supported by the Portuguese Foundation for Science and Technology (Projects: UIDB/00009/2020; UIDP/00009/2020). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Antiviral Action against SARS-CoV-2 of a Synthetic Peptide Based on a Novel Defensin Present in the Transcriptome of the Fire Salamander (Salamandra salamandra).

The potential emergence of zoonotic diseases has raised significant concerns, particularly in light of the recent pandemic, emphasizing the urgent need for scientific preparedness. The bioprospection and characterization of new molecules are strategically relevant to the research and development of innovative drugs for viral and bacterial treatment and disease management. Amphibian species possess a diverse array of compounds, including antimicrobial peptides. This study identified the first bioactive peptide from Salamandra salamandra in a transcriptome analysis. The synthetic peptide sequence, which belongs to the defensin family, was characterized through MALDI TOF/TOF mass spectrometry. Molecular docking assays hypothesized the interaction between the identified peptide and the active binding site of the spike WT RBD/hACE2 complex. Although additional studies are required, the preliminary evaluation of the antiviral potential of synthetic SS-I was conducted through an in vitro cell-based SARS-CoV-2 infection assay. Additionally, the cytotoxic and hemolytic effects of the synthesized peptide were assessed. These preliminary findings highlighted the potential of SS-I as a chemical scaffold for drug development against COVID-19, hindering viral infection. The peptide demonstrated hemolytic activity while not exhibiting cytotoxicity at the antiviral concentration.

Thermal properties of nanofluids using hydrophilic and hydrophobic LiYF4:Yb/Er upconverting nanoparticles.

Luminescent nanoparticles have shown great potential for thermal sensing in bio-applications. Nonetheless, these materials lack water dispersibility that can be overcome by modifying their surface properties with water dispersible molecules such as cysteine. Herein, we employ LiYF4:Er3+/Yb3+ upconverting nanoparticles (UCNPs) capped with oleate or modified with cysteine dispersed in cyclohexane or in water, respectively, as thermal probes. Upconversion emission was used to sense temperature with a relative thermal sensitivity of ∼1.24% K-1 (at 300 K) and a temperature uncertainty of 0.8 K for the oleate capped and of 0.5 K for cysteine modified NPs. To study the effect of the cysteine modification in the heat transfer processes, the thermal conductivity of the nanofluids was determined, yielding 0.123(6) W m-1 K-1 for the oleate capped UCNPs dispersed in cyclohexane and 0.50(7) W m-1 K-1 for the cysteine modified UCNPs dispersed in water. Moreover, through the heating curves, the nanofluids' thermal resistances were estimated, showing that the cysteine modification partially prevents heat transfer.

Surgical aortic valve replacement in octogenarians: Single-center perioperative outcomes and five-year survival.

INTRODUCTION AND OBJECTIVES: Aortic stenosis is the most common valvular heart disease. The number of octogenarians proposed for intervention is growing due to increased lifespan. In this manuscript we aim to evaluate perioperative outcome and long-term survival after surgical aortic valve replacement (SAVR) in octogenarians, comparing patients with low surgical risk (EuroscoreII <4%) with intermediate-high risk (EuroscoreII ≥4%). METHODS: A retrospective observational single-center cohort study with 195 patients aged ≥80 years old, who underwent SAVR between 2017 and 2021, was conducted. Patients were divided into two groups according to EuroscoreII: (1) Low risk (EuroscoreII <4%) with intermediate-high risk (EuroscoreII ≥4%). Continuous variables are presented in median (IQR), analyzed using Wilcoxon rank sum test; categorical variables in percentages, analyzed using chi-squared test; and survival was analyzed by Kaplan-Meier, open cohort, and the log-rank test was performed. RESULTS: The overall median age was 82 (IQR 81-83), with 4.6% of the patients ≥85 years old. 23.6% of the patients presented EuroscoreII ≥4%. No complications were observed in 26.2%, with a significantly higher rate in intermediate-high risk patients. Postoperative need for hemodynamic support was the most frequent complication, followed by postoperative acute kidney injury and the use of blood products. Overall median ICU stay was three days (2-4) and hospital length of stay (LOS) six days (5-8). Patients with intermediate-high risk and those with complications had longer ICU LOS. At 12 months, overall survival was 96.4%, at three years 94.1% and 5 years 75.4%. Patients with low surgical risk had higher survival proportions up to 5 years. CONCLUSION: SAVR in patients ≥80 years is associated with low in-hospital mortality, although a significant proportion of patients develop complications. Long-term follow-up up to five years after surgery is acceptable in octogenarians with low surgical risk.

The Role of 5-Hydroxymethylcytosine as a Potential Epigenetic Biomarker in a Large Series of Thyroid Neoplasms.

Cytosine modifications at the 5-carbon position play a critical role in gene expression regulation and have been implicated in cancer development. 5-Hydroxymethylcytosine (5hmC), arising from 5-methylcytosine (5-mC) oxidation, has shown promise as a potential malignancy marker due to its depletion in various human cancers. However, its significance in thyroid tumors remains underexplored, primarily due to limited data. In our study, we evaluated 5hmC expression levels by immunohistochemistry in a cohort of 318 thyroid tumors. Our analysis revealed significant correlations between 5hmC staining extension scores and nodule size, vascular invasion, and oncocytic morphology. Nuclear 5hmC staining intensity demonstrated associations with focality, capsule status, extrathyroidal extension, vascular invasion, and oncocytic morphology. Follicular/oncocytic adenomas exhibited higher 5hmC expression than uncertain malignant potential (UMP) or noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), as well as malignant neoplasms, including papillary thyroid carcinomas (PTCs), oncocytic carcinomas (OCAs), follicular thyroid carcinomas (FTCs), and invasive encapsulated follicular variants of PTC (IEFV-PTC). TERT promoter mutation cases showed notably lower values for the 5hmC expression, while RAS (H, N, or K) mutations, particularly HRAS mutations, were associated with higher 5hmC expression. Additionally, we identified, for the first time, a significant link between 5hmC expression and oncocytic morphology. However, despite the merits of these discoveries, we acknowledge that 5hmC currently cannot segregate minimally invasive from widely invasive tumors, although 5hmC levels were lower in wi-FPTCs. Further research is needed to explore the potential clinical implications of 5hmC in thyroid tumors.

Consumer Knowledge about Dietary Relevance of Fruits and Vegetables: A Study Involving Participants from Portugal and France.

Fruits and vegetables are recommended as low-calorie foods that contribute to the proper intake of necessary micronutrients, macronutrients, and bioactive compounds with health benefits. However, the recommendations for the dietary intake of these foods fail to be attained in most European countries. For this reason, promoting more knowledge about the health effects of fruits and vegetables is essential to decrease the incidence of chronic diseases. This study was conducted to investigate the knowledge of the health benefits of fruits and vegetables among the population of Portugal and France. The present work involved a questionnaire survey of 639 participants (257 from Portugal and 382 from France). The results revealed that most participants were young females (68.9%) with good education (76%) and an average weight range. They consumed a varied diet (57%) but had body dissatisfaction (63.2%). The respondents had good knowledge about the health effects of fruits and vegetables. However, the French population knew more about the theme than the Portuguese. Portuguese individuals were more likely to have incomplete information. Gender and education significantly influenced knowledge levels, with females and highly educated individuals demonstrating greater understanding. Dissatisfaction with body weight drives individuals to seek nutrition information. This investigation enhances our comprehension of the factors that affect knowledge of vegetable and fruit consumption among young adults in Portugal and France. Moreover, it highlights the importance of implementing focused educational programs to enhance nutrition literacy, particularly for less-aware demographic groups. Going forward, a more in-depth analysis of these factors could assist in creating more efficient strategies to encourage healthier dietary habits and improve nutrition literacy among these communities.

rec-1 loss of function increases recombination in the central gene clusters at the expense of autosomal pairing centers.

Meiotic control of crossover (CO) number and position is critical for homologous chromosome segregation and organismal fertility, recombination of parental genotypes, and the generation of novel genetic combinations. We here characterize the recombination rate landscape of a rec-1 loss of function modifier of CO position in Caenorhabditis elegans, one of the first ever modifiers discovered. By averaging CO position across hermaphrodite and male meioses and by genotyping 203 single-nucleotide variants covering about 95% of the genome, we find that the characteristic chromosomal arm-center recombination rate domain structure is lost in the loss of function rec-1 mutant. The rec-1 loss of function mutant smooths the recombination rate landscape but is insufficient to eliminate the nonuniform position of CO. Lower recombination rates in the rec-1 mutant are particularly found in the autosomal arm domains containing the pairing centers. We further find that the rec-1 mutant is of little consequence for organismal fertility and egg viability and thus for rates of autosomal nondisjunction. It nonetheless increases X chromosome nondisjunction rates and thus male appearance. Our findings question the maintenance of recombination rate heritability and genetic diversity among C. elegans natural populations, and they further suggest that manipulating genetic modifiers of CO position will help find quantitative trait loci located in low-recombining genomic regions normally refractory to discovery.

Enhancing skeletal stability and Class III correction through active orthodontist engagement in virtual surgical planning: A voxel-based 3-dimensional analysis.

INTRODUCTION: Skeletal stability after bimaxillary surgical correction of Class III malocclusion was investigated through a qualitative and quantitative analysis of the maxilla and the distal and proximal mandibular segments using a 3-dimensional voxel-based superimposition among virtual surgical predictions performed by the orthodontist in close communication with the maxillofacial surgeon and 12-18 months postoperative outcomes. METHODS: A comprehensive secondary data analysis was conducted on deidentified preoperative (1 month before surgery [T1]) and 12-18 months postoperative (midterm [T2]) cone-beam computed tomography scans, along with virtual surgical planning (VSP) data obtained by Dolphin Imaging software. The sample for the study consisted of 17 patients (mean age, 24.8 ± 3.5 years). Using 3D Slicer software, automated tools based on deep-learning approaches were used for cone-beam computed tomography orientation, registration, bone segmentation, and landmark identification. Colormaps were generated for qualitative analysis, whereas linear and angular differences between the planned (T1-VSP) and observed (T1-T2) outcomes were calculated for quantitative assessments. Statistical analysis was conducted with a significance level of α = 0.05. RESULTS: The midterm surgical outcomes revealed a slight but significantly less maxillary advancement compared with the planned position (mean difference, 1.84 ± 1.50 mm; P = 0.004). The repositioning of the mandibular distal segment was stable, with insignificant differences in linear (T1-VSP, 1.01 ± 3.66 mm; T1-T2, 0.32 ± 4.17 mm) and angular (T1-VSP, 1.53° ± 1.60°; T1-T2, 1.54° ± 1.50°) displacements (P >0.05). The proximal segments exhibited lateral displacement within 1.5° for both the mandibular right and left ramus at T1-VSP and T1-T2 (P >0.05). CONCLUSIONS: The analysis of fully digital planned and surgically repositioned maxilla and mandible revealed excellent precision. In the midterm surgical outcomes of maxillary advancement, a minor deviation from the planned anterior movement was observed.

Non-News Websites Expose People to More Political Content Than News Websites: Evidence from Browsing Data in Three Countries.

Most scholars focus on the prevalence and democratic effects of (partisan) news exposure. This focus misses large parts of online activities of a majority of politically disinterested citizens. Although political content also appears outside of news outlets and may profoundly shape public opinion, its prevalence and effects are under-studied at scale. This project combines three-wave panel survey data from three countries (total N = 7,266) with online behavioral data from the same participants (over 106M visits). We create a multi-lingual classifier to identify political content both in news and outside (e.g. in shopping or entertainment sites). We find that news consumption is infrequent: just 3.4% of participants' online browsing comprised visits to news sites. Only between 14% (NL) and 36% (US) of these visits were to news about politics. The overwhelming majority of participants' visits were to non-news sites. Although only 1.6\% of those visits related to politics, in absolute terms, citizens encounter politics more frequently outside of news than within news. Out of every 10 visits to political content, 3.4 come from news and 6.6 from non-news sites. Furthermore, exposure to political content outside news domains had the same - and in some cases stronger - associations with key democratic attitudes and behaviors as news exposure. These findings offer a comprehensive analysis of the online political (not solely news) ecosystem and demonstrate the importance of assessing the prevalence and effects of political content in non-news sources.

Acute Hepatitis E-Associated Guillain-Barré Syndrome.

Guillain-Barré syndrome (GBS) is a rare autoimmune disorder of the peripheral nervous system that causes progressive weakness and sensory disturbances, usually following an infection or immunization. It has been associated with multiple causes, including bacterial and viral infections. Hepatitis E virus (HEV) is a common cause of acute viral hepatitis that can rarely develop neurological complications. We report a case of a 72-year-old man who developed GBS secondary to an acute HEV infection. He presented with numbness and weakness of the lower limbs that rapidly evolved into respiratory failure requiring mechanical ventilation and intravenous immunoglobulin therapy (IVIg). This case adds to the literature on the association between HEV infection and GBS and the importance of early detection of this rapidly progressive condition.