Effectiveness and safety of liposomal rapamycin for the treatment of facial angiofibromas in tuberous sclerosis.

AIM: Topical rapamycin is the pharmacological treatment of choice for facial angiofibromas in rare tuberous sclerosis disease. A new, more advanced, and complex formula was developed in our pharmacy service: rapamycin 0.4% liposomal formulation, with better organoleptic characteristics and a more favorable release profile of the active ingredient. The purpose of this study is to evaluate the effectiveness and safety of liposomal topical rapamycin for the treatment of facial injuries in this rare disease. METHOD: This was an observational, prospective, and multicenter study. Effectiveness was evaluated mainly through facial angiofibromas severity index (FASI), investigator's global assessment (IGA) scores, and dermatology life quality index (DLQI) questionnaire. To assess the safety profile of rapamycin, adverse reactions were reported, and blood tests and blood rapamycin levels were performed during treatment. RESULTS: Eleven patients were included, of which 8/11 (73%) patients obtained successful treatment according to FASI and IGA scores after 24 weeks of treatment. Statistical analysis demonstrated a significant improvement (p<.05) in FASI and IGA scores, erythema, and FA size after treatment with rapamycin liposomal formulation (FASI before treatment, median (interquartile range): 6.0 (2.0), FASI after treatment: 3.5 (2.0), p=.0063). Five patients also improved their quality of life after treatment. Regarding safety profile of rapamycin, the most common adverse reaction was mild pruritus and 2 patients reported erythema, who discontinued treatment prematurely. All hematological tests were normal, and blood rapamycin levels were undetectable. CONCLUSIONS: After galenic improvements and clinical evaluations, the rapamycin liposomal formulation proved to be effective and safe for this therapeutic indication. This new formulation was included as a magistral formula in our hospital pharmacy service, now accessible for prescribing by dermatologists. Drug development in hospital pharmacy is often the only pharmacological alternative available to treat the symptoms of rare diseases, when treatment options are limited or inadequate.

Immune response against the SARS-CoV-2 spike protein in cancer patients after COVID-19 vaccination during the Omicron wave: a prospective study.

BACKGROUND: Cancer patients often have weakened immune systems, resulting in a lower response to vaccines, especially those receiving immunosuppressive oncological treatment (OT). We aimed to assess the impact of OT on the humoral and T-cell response to the B.1 lineage and Omicron variant following COVID-19 vaccination in patients with solid and hematological neoplasms. METHODS: We conducted a prospective study on cancer patients, stratified into OT and non-OT groups, who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. The outcomes measured were the humoral (anti-SARS-CoV-2 S IgG titers and ACE2-S interaction inhibition capacity) and cellular (SARS-CoV-2 S-specific T-cell spots per million PBMCs) responses against the B.1 lineage and Omicron variant. These responses were evaluated four weeks after the second dose (n = 98) and eight weeks after the booster dose (n = 71). RESULTS: The humoral response after the second vaccine dose against the B.1 lineage and Omicron variant was significantly weaker in the OT group compared to the non-OT group (q-value<0.05). A booster dose of the mRNA-1273 vaccine significantly improved the humoral response in the OT group, making it comparable to the non-OT group. The mRNA-1273 vaccine, designed for the original Wuhan strain, elicited a weaker humoral response against the Omicron variant compared to the B.1 lineage, regardless of oncological treatment or vaccine dose. In contrast, T-cell responses against SARS-CoV-2, including the Omicron variant, were already present after the second vaccine dose and were not significantly affected by oncological treatments. CONCLUSIONS: Cancer patients, particularly those receiving immunosuppressive oncological treatments, should require booster doses and adapted COVID-19 vaccines for new SARS-CoV-2 variants like Omicron. Future studies should evaluate the durability of the immune response and the efficacy of individualized regimens.

Conventional Radiography Assessment of the Pediatric Knee: Pearls and Pitfalls.

Knee pain is one of the most common indications for radiography in the evaluation of musculoskeletal disorders in children and adolescents. According to international guidelines, knee radiographs should be obtained when there is the suspicion of an effusion, limited motion, pain to palpation, inability to bear weight, mechanical symptoms (such as "locking"), and persistent knee pain after therapy. When indicated, radiographs can provide crucial information for the clinical decision-making process. Because of the developmental changes occurring in the knee during growth, the assessment of knee radiographs can be challenging in children and adolescents. Radiologists unfamiliar with the appearance of the knee on radiographs during skeletal maturation risk overcalling or overlooking bone lesions. Image acquisition techniques and parameters should be adapted to children. This article describes the most common challenges in distinguishing pathology from the normal appearance of knee radiographs in the pediatric population, offering some pearls and pitfalls that can be useful in clinical practice.

Spin-Orbit Torque in Single-Molecule Junctions from ab Initio.

The use of electric fields applied across magnetic heterojunctions that lack spatial inversion symmetry has been previously proposed as a nonmagnetic means of controlling localized magnetic moments through spin-orbit torques (SOT). The implementation of this concept at the single-molecule level has remained a challenge, however. Here, we present first-principles calculations of SOT in a single-molecule junction under bias and beyond linear response. Employing a self-consistency scheme invoking density functional theory and nonequilibrium Green's function theory including spin-orbit interaction, we compute the change of the magnetization with the bias voltage and the associated current-induced SOT. Within the linear regime our quantitative estimates for the SOT in single-molecule junctions yield values similar to those known for magnetic interfaces. Our findings contribute to an improved microscopic understanding of SOT in single molecules.

Strongly Bound Excitons and Anisotropic Linear Absorption in Monolayer Graphullerene.

Graphullerene is a novel two-dimensional carbon allotrope with unique optoelectronic properties. Despite significant experimental characterization and prior density functional theory calculations, unanswered questions remain as to the nature, energy, and intensity of the electronic and optical excitations. Here, we present first-principles calculations of the quasiparticle band structure, neutral excitations, and absorption spectra of monolayer graphullerene and bulk graphullerite, employing the GW-Bethe-Salpeter equation (GW-BSE) approach. We show that strongly bound excitons dominate the absorption spectrum of monolayer graphullerene with binding energies up to 0.8 eV, while graphullerite exhibits less pronounced excitonic effects. Our calculations also reveal a strong linear polarization anisotropy, reflecting the in-plane structural anisotropy from intermolecular coupling between neighboring C60 units. We further show that the presence of Mg atoms, crucial to the synthesis process, induces structural modifications and polarizability effects, resulting in a ∼1 eV quasiparticle gap renormalization and a reduction in the exciton binding energy to ∼0.6 eV.

The beauty of pediatric musculoskeletal ultrasound.

Ultrasound is a powerful technique in pediatric imaging and musculoskeletal (MSK) imaging in many specific clinical scenarios. This article will feature some common and less common spot diagnoses in pediatric musculoskeletal ultrasound.Cases were collected by members of the Educational Committee of the ESSR (European Society of musculoSkeletal Radiology) and the Pediatric Subcommittee of the ESSR with expertise in musculoskeletal ultrasound.Fifteen clinical entities are discussed based on the features that allow diagnosis by ultrasound.Clinical history, location, and ultrasound appearance are the keys to spot diagnoses when performing pediatric musculoskeletal ultrasound. · Ultrasound in pediatric musculoskeletal imaging can achieve a diagnosis in specific clinical settings.. · Clinical history, location, and ultrasound appearance are keys to spot diagnoses.. · Knowledge of spot diagnoses in pediatric musculoskeletal ultrasound facilitates daily clinical practice..

Comparative Clinical Study of Two Tooth Whitening Protocols. A Randomized Clinical Trial. Part 2.

This study aimed to clinically evaluate the efficacy of two different home whitening protocols and to determine which is more effective: applying the whitening gel every 48 hours or every 72 hours for 6 weeks. The differences in terms of tooth sensitivity are also analyzed. A sample of 72 patients was randomly divided into 3 groups of 24 (N=24). Group A: 16% carbamide peroxide applied every 48h for 6 weeks. Group B: 16% carbamide peroxide applied every 72h for 6 weeks. Group C (control group): a placebo gel without peroxide (glycerin gel) was applied every 48h for 6 weeks. To compare the groups, color measurements were made using a spectrophotometer and ANOVA test and Bonferroni test was used. The confidence level was set at 95% (p ≤ 0.05) and no statistically significant differences between applying 16% carbamide peroxide every 48h or every 72h for 6 weeks (p> 0.05) were found. The study concluded that carbamide peroxide 16% is equally effective applied with both protocols, obtaining the same results.

Taxonomic distinctness and diversity patterns of a polychaete (Annelida) community on the continental shelf of the Southern Gulf of Mexico.

The spatial patterns of taxonomic diversity of annelid polychaete species from the continental shelf in the Southern Gulf of Mexico were examined in this study. We used taxonomic distinctness and its spatial variations to explore the diversity patterns and how they change between Southern Gulf of Mexico regions. In addition, using taxonomic distinctness as a dissimilarity measure and Ward's Clustering, we characterized three distinct faunal assemblages. We also investigated patterns of richness, taxonomic distinctness, and distance decay of similarity between sampling stations as a ß-diversity measure. Finally, we examined the spatial relationships between polychaete assemblages and environmental variables to test the relative importance of spatial and environmental components in annelid polychaete community structure from the Southern Gulf of Mexico. We used a combination of eigenvector-based multivariate analyses (dbMEMs) and distance-based redundancy analysis (dbRDA) to quantify the relative importance of these explanatory variables on the spatial variations of taxonomic distinctness. The significance level of spatial and environmental components to the distribution of polychaete species showed that the combined effect of spatial processes and sediment characteristics explained a higher percentage of the variance than those parameters could alone.

In vitro 3D co-culture model of human endothelial and smooth muscle cells to study pathological vascular remodeling. / Modelo de cocultivo 3D in vitro de células endoteliales y vasculares de músculo liso humanas para el estudio del remodelado vascular patológico.

Pathological vascular remodeling of the vessel wall refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease. The vessel wall is composed of two main types of cells, endothelial cells and vascular smooth muscle cells, whose communication is crucial in both the development of the vasculature and the homeostasis of mature vessels. Changes in the dialogue between endothelial cells and vascular smooth muscle cells are associated with various pathological states that triggers remodeling of the vascular wall. For many years, considerable efforts have been made to develop effective diagnoses and treatments for these pathologies by studying their mechanisms in both in vitro and in vivo models. Compared to animal models, in vitro models can provide great opportunities to obtain data in a more homogeneous, economical and massive way, providing an overview of the signaling pathways responsible for these pathologies. The implementation of three-dimensional in vitro co-culture models for the study of other pathologies has been postulated as a potentially applicable methodology, which determines the importance of its application in studies of cardiovascular diseases. In this article we present a method for culturing human endothelial cells and vascular smooth muscle cells, grown under non-adherent conditions, that generate three-dimensional spheroidal structures with greater physiological equivalence to in vivo conditions. This in vitro modeling could be used as a study tool to identify cellular and molecular mechanisms involved in the pathological processes underlying vascular remodeling.

Nanosilver-based materials as feed additives: Evaluation of their transformations along in vitro gastrointestinal digestion in pigs and chickens by using an ICP-MS based analytical platform.

The use of a new nanomaterial in the feed chain requires a risk assessment that involves in vitro gastrointestinal digestions to predict its degradation and oral exposure to nanoparticles. In this study, a nanosilver-based material was incorporated into pig and chicken feed as a growth-promoting additive and subjected to the corresponding in vitro gastrointestinal digestions. An inductively coupled plasma mass spectroscopy (ICP-MS) analytical platform was used to obtain information about the silver released in the different digestion phases. It included conventional ICP-MS for total silver determination, but also single particle ICP-MS and coupling to hydrodynamic chromatography for detection of dissolved and particulate silver. The bioaccessible fraction in the intestinal phase accounted for 8-13% of the total silver, mainly in the form of dissolved Ag(I) species, with less than 0.1% as silver-containing particles. Despite the additive behaving differently in pig and chicken digestions, the feed matrix played a relevant role in the fate of the silver.

Innate biosignature of treatment failure in human cutaneous leishmaniasis.

The quality and magnitude of the immune and inflammatory responses determine the clinical outcome of Leishmania infection, and contribute to the efficacy of antileishmanial treatments. However, the precise immune mechanisms involved in healing or in chronic immunopathology of human cutaneous leishmaniasis (CL) are not completely understood. Through sequential transcriptomic profiling of blood monocytes (Mo), neutrophils (Nφ), and eosinophils (Eφ) over the course of systemic treatment with meglumine antimoniate, we discovered that a heightened and sustained Type I interferon (IFN) response signature is a hallmark of treatment failure (TF) in CL patients. The transcriptomes of pre-treatment, mid-treatment and end-of-treatment samples were interrogated to identify predictive and prognostic biomarkers of TF. A composite score derived from the expression of 9 differentially expressed genes (common between Mo, Nφ and Eφ) was predictive of TF in this patient cohort for biomarker discovery. Similarly, machine learning models constructed using data from pre-treatment as well as post-treatment samples, accurately classified treatment outcome between cure and TF. Results from this study instigate the evaluation of Type-I IFN responses as new immunological targets for host-directed therapies for treatment of CL, and highlight the feasibility of using transcriptional signatures as predictive biomarkers of outcome for therapeutic decision making.

Measured and Estimated Glomerular Filtration Rate to Evaluate Rapid Progression and Changes over Time in Autosomal Polycystic Kidney Disease: Potential Impact on Therapeutic Decision-Making.

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (-3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.

What Is Considered Healthy Eating? An Exploratory Study among College Students of Nutrition and Food Science.

In modern industrialized societies, the focus on healthy eating has increased significantly across multiple sectors, including the media, public policy, expert opinion, and public awareness. The aim of this research was to explore the perceptions of healthy eating and the barriers to adopting a healthy diet among undergraduate students in Human Nutrition and Dietetics (HND) and Food Science and Technology (FST) degrees in Spain. An exploratory and descriptive cross-sectional study was conducted using a qualitative and quantitative methodology and convenience sampling. Two focus groups and a questionnaire were utilized (300 participants from all academic years completed the survey). Differences in definitions of healthy eating and perceived barriers were found between genders and students at different stages of training (p < 0.05). In their understanding of healthy eating, the students placed importance on balance, variety, moderation, and individual factors. Although students considered it easy to follow a healthy diet, family's eating habits, time availability, and emotional states were found to be the main barriers to the implementation of healthy practices. The obtained data supports the need to critically address perceptions of healthy eating throughout the training of nutrition and food science professionals. The insights obtained on the perceived barriers highlight the importance of considering both individual and environmental factors.

Reducing Recurrent Urinary Tract Infections in Women with MV140 Impacts Personal Burden of Disease: Secondary Analyses of a Randomized Placebo-controlled Efficacy Study.

Background: Recurrent urinary tract infection (rUTI) remains a major health burden for women. A randomized, double-blind, placebo-controlled trial (RCT; NCT02543827) reported that female patients with rUTI receiving a sublingual vaccine, MV140, had a reduction in rUTI and increase in UTI-free rate compared with placebo. Objective: To determine the impact of MV140 on the personal burden of disease in women with rUTI using secondary endpoint data from the pivotal RCT evaluating MV140. Design setting and participants: In the primary RCT, female patients with rUTI enrolled in Spain and UK (from October 2015 to April 2019) were randomized to placebo (6 mo) or MV140 (3 or 6 mo), and followed for 12 mo. Individuals analyzed in this secondary analysis included those in the placebo and 3-mo (recommended dose) groups. Intervention: A polybacterial sublingual vaccine, MV140 (four inactivated whole-cell bacteria-Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Enterococcus faecalis), or placebo. Outcome measurements and statistical analysis: Symptom severity scoring, antibiotic use, safety, and multiple aspects of quality of life (QoL; Short-Form Questionnaire [SF-36]) were assessed. Results and limitations: Compared with the placebo group (n = 76), the 3-mo vaccinated group (n = 74) experienced fewer overall UTI symptoms (mean symptom score 102.2 ± 222.9 vs 194.2 ± 178.8; p = 0.0002), fewer days on antibiotics (12.4 ± 17.7 vs 28.7 ± 25.2; p = 0.0001), and improved total, general, and physical SF-36 QoL improvement (differences in means for total SF-36 score 15.7; 95% confidence interval [CI] 8.80, 22.64; p < 0.0001), with only social function QoL showing no impact (4.07; 95% CI -4.93, 13.08; p = 0.3744). Conclusions: Three months of MV140 is associated with a reduction of the personal burden of UTI by reducing overall UTI symptoms and antibiotic use, improving QoL in women with rUTI. Patient summary: Three months of MV140 vaccine, which has previously been shown to reduce the risk of urinary tract infection safely, is associated with a reduction in the personal burden of disease.

Hearing Performance in Cochlear Implant Users Who Have Facial Nerve Stimulation.

Introduction Facial nerve stimulation (FNS) is a complication in cochlear implant (CI) when the electrical current escapes from the cochlea to the nearby facial nerve. Different management to reduce its effects are available, although changes might result in a less-than-ideal fitting for the CI user, eventually reducing speech perception. Objective To verify the etiologies that cause FNS, to identify strategies in managing FNS, and to evaluate speech recognition in patients who present FNS. Methods Retrospective study approved by the Ethical Board of the Institution. From the files of a CI group, patients who were identified with FNS either during surgery or at any time postoperatively were selected. Data collection included: CI manufacturer, electrode array type, age at implantation, etiology of hearing loss, FNS identification date, number of electrodes that generated FNS, FNS management actions, and speech recognition in quiet and in noise. Results Data were collected from 7 children and 25 adults. Etiologies that cause FNS were cochlear malformation, head trauma, meningitis, and otosclerosis; the main actions included decrease in the stimulation levels followed by the deactivation of electrodes. Average speech recognition in quiet before FNS was 86% and 80% after in patients who were able to accomplish the test. However, there was great variability, ranging from 0% in quiet to 90% of speech recognition in noise. Conclusion Etiologies that cause FNS are related to cochlear morphology alterations. Facial nerve stimulation can be solved using speech processor programming parameters; however, it is not possible to predict outcomes, since results depend on other variables.

Feasibility of a capacity building organizational intervention for worker safety and well-being in the transportation industry: Pivoting to address the COVID-19 pandemic and social and political unrest in Chile.

OBJECTIVE: This study developed, implemented, and evaluated the feasibility of executing an organizational capacity building intervention to improve bus driver safety and well-being in a Chilean transportation company. METHOD: Through an implementation science lens and using a pre-experimental mixed methods study design, we assessed the feasibility of implementing a participatory organizational intervention designed to build organizational capacity. RESULT: We identified contextual factors that influenced the intervention mechanisms and intervention implementation and describe how the company adapted the approach for unexpected external factors during the COVID-19 pandemic and social and political unrest experienced in Chile. CONCLUSIONS: The intervention enabled the organization to create an agile organizational infrastructure that provided the organization's leadership with new ways to be nimbler and more responsive to workers' safety and well-being needs and was robust in responding to strong external forces that were undermining worker safety and well-being.

Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination.

Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the posttranslational modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a notable absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Our data indicate that neddylation exerts a global influence on the complex transcriptional and posttranscriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signaling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.

Autochthonous Wheat Grown in Organic and Conventional Systems: Nutritional Quality of Flour and Bread.

A growing interest in the recovery and enhancement of crops, particularly local varieties such as 'Caaveiro' wheat, has been observed. This study aims to investigate the impact of cultivation systems (organic versus conventional) on the nutritional quality of 'Caaveiro' flour and breads protected by the PGI "Pan Galego," employing two fermentation methods (sourdough versus sourdough and biological yeast). Organic flour exhibited significantly higher levels of moisture, fat, sucrose, phosphorus (P), sodium (Na), and copper (Cu) while also exhibiting a lower total starch and zinc (Zn) content. Organic bread, produced using both fermentation methods, demonstrated significantly higher protein, carbohydrate, total, resistant, and rapidly digestible starch, ash, Na, P, iron (Fe), and Cu content. Additionally, they contained less moisture compared to conventional bread. Despite variations in nutritional characteristics based on the cultivation system, the organic approach proved effective at producing high-quality products with a positive environmental impact, which is highly appreciated by consumers.

Conformational Defects in the Limbs of Menorca Purebred Horses and Their Relationship to Functionality.

Limb-conformation defects significantly influence equine performance and welfare, necessitating thorough investigation for effective management. This study examines the prevalence and genetic parameters of 14 limb-conformation defects in Menorca Purebred horses using data from 1120 records (509 animals with an average age of 101.87 ± 1.74 months) collected between 2015 and 2023. Defects were evaluated using a three-class scale by three appraisers, and a Bayesian approach via Gibbs sampling was employed to estimate genetic parameters including gender, birth period, stud selection criteria, evaluation age and appraiser as fixed effects. Splay-footed forelimb and closed hocks were the most prevalent defects (67.20% and 62.53%, respectively). Horses with any of the defects analyzed have been observed to obtain significantly lower scores for both walk and trot. Heritability estimates range from 0.12 (s.d.: 0.025) for closed hock to 0.30 (s.d.: 0.054) for base narrow, confirming the genetic influences on the expression of limb conformation defects. The divergent defect in hind limbs showed the highest genetic correlations with forelimb defects (camped under, -0.69; s.d: 0.32 and camped out, 0.70; s.d: 0.27). The significant genetic correlations between defects highlight the complexity of the relationships, which requires careful consideration.