Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway.

Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.

Optimizing the Catalytic Performance of Ba1-xCexMnO3 and Ba1-xLaxCu0.3Mn0.7O3 Perovskites for Soot Oxidation in Simulated GDI Exhaust Conditions.

Ba1-xCexMnO3 (BM-Cex) and Ba1-xLaxMn0.7Cu0.3O3 (BMC-Lax) perovskite-type mixed oxides were synthesized using the sol-gel method adapted for aqueous media with different values of x (0, 0.1, 0.3, 0.6) to estimate the effect of the degree of the partial substitution of Ba by Ce or La on the structure and properties that are relevant for their use as catalysts for gasoline direct injection (GDI) soot oxidation. The samples were deeply characterized by ICP-OES, XRD, XPS, N2 adsorption, H2-TPR, and O2-TPD, and their potential as catalysts for soot oxidation has been analyzed in various scenarios that replicate the exhaust conditions of a GDI engine. By comparing the catalytic performance for soot oxidation of the two tested series (BM-Cex and BMC-Lax) and in the two conditions used (100% He and 1% O2 in He), it could be concluded that (i) in the absence of oxygen in the reaction atmosphere (100% He), BMC-La0.1 is the best catalyst, as copper is also able to catalyze the soot oxidation; and (ii) if oxygen is present in the reaction atmosphere (1% O2/He), BM-Ce0.1 is the most-active catalyst as it presents a higher proportion of Mn(IV) than BMC-La0.1. Thus, it seems that the addition of an amount of Ce or La higher than that corresponding to x = 0.1 in Ba1-xCexMnO3 and Ba1-xLaxCu0.3Mn0.7O3 does not allow us to improve the catalytic performance of BM-Ce0.1 and BMC-La0.1 for soot oxidation in the tested conditions.

Dietary fiber monosaccharide content alters gut microbiome composition and fermentation.

Members of the mammalian gut microbiota metabolize diverse complex carbohydrates that are not digested by the host, which are collectively labeled "dietary fiber." While the enzymes and transporters that each strain uses to establish a nutrient niche in the gut are often exquisitely specific, the relationship between carbohydrate structure and microbial ecology is imperfectly understood. The present study takes advantage of recent advances in complex carbohydrate structure determination to test the effects of fiber monosaccharide composition on microbial fermentation. Fifty-five fibers with varied monosaccharide composition were fermented by a pooled feline fecal inoculum in a modified MiniBioReactor array system over a period of 72 hours. The content of the monosaccharides glucose and xylose was significantly associated with the reduction of pH during fermentation, which was also predictable from the concentrations of the short-chain fatty acids lactic acid, propionic acid, and the signaling molecule indole-3-acetic acid. Microbiome diversity and composition were also predictable from monosaccharide content and SCFA concentration. In particular, the concentrations of lactic acid and propionic acid correlated with final alpha diversity and were significantly associated with the relative abundance of several of the genera, including Lactobacillus and Dubosiella. Our results suggest that monosaccharide composition offers a generalizable method to compare any dietary fiber of interest and uncover links between diet, gut microbiota, and metabolite production. IMPORTANCE: The survival of a microbial species in the gut depends on the availability of the nutrients necessary for that species to survive. Carbohydrates in the form of non-host digestible fiber are of particular importance, and the set of genes possessed by each species for carbohydrate consumption can vary considerably. Here, differences in the monosaccharides that are the building blocks of fiber are considered for their impact on both the survival of different species of microbes and on the levels of microbial fermentation products produced. This work demonstrates that foods with similar monosaccharide content will have consistent effects on the survival of microbial species and on the production of microbial fermentation products.

Light-activated conjugated polymer nanoparticles to defeat pathogens associated with bovine mastitis.

Bovine mastitis (BM) represents a significant challenge in the dairy industry. Limitations of conventional treatments have prompted the exploration of alternative approaches, such as photodynamic inactivation (PDI). In this study, we developed a PDI protocol to eliminate BM-associated pathogens using porphyrin-doped conjugated polymer nanoparticles (CPN). The PDI-CPN protocol was evaluated in four mastitis isolates of Staphylococcus and in a hyper-biofilm-forming reference strain. The results in planktonic cultures demonstrated that PDI-CPN exhibited a bactericidal profile upon relatively low light doses (∼9.6 J/cm2). Furthermore, following a seven-hour incubation period, no evidence of cellular reactivation was observed, indicating a highly efficient post-photodynamic inactivation effect. The successful elimination of bacterial suspensions encouraged us to test the PDI-CPN protocol on mature biofilms. Treatment using moderate light dose (∼64.8 J/cm2) reduced biofilm biomass and metabolic activity by up to 74% and 88%, respectively. The impact of PDI-CPN therapy on biofilms was investigated using scanning electron microscopy (SEM), which revealed nearly complete removal of the extracellular matrix and cocci. Moreover, ex vivo studies conducted on bovine udder skin demonstrated the efficacy of the therapy in eliminating bacteria from these scaffolds and its potential as a prophylactic method. Notably, the histological analysis of skin revealed no signs of cellular degeneration, suggesting that the protocol is safe and effective for BM treatment. Overall, this study demonstrates the potential of PDI-CPN in treating and preventing BM pathogens. It also provides insights into the effects of PDI-CPN on bacterial growth, metabolism, and survival over extended periods, aiding the development of effective control strategies and the optimization of future treatments.

Farmed fish welfare research status in Latin America: A review.

Latin America (LATAM) plays an important role in the world's production of aquatic animals and is the second most productive region in the world. Chile, Ecuador, Brazil, Mexico, Colombia, and Perú contribute 87% of LATAM aquaculture production. The fish welfare in aquaculture is of increasing public concern globally, and LATAM is no exception, growing in importance for fish farmers, authorities, and scientists. Although the topic is somewhat controversial, the welfare status of farmed fish has direct implications for their production and the sustainability of the industry. Therefore, this study analyses scientific papers on animal welfare in farmed fish, from the six countries in LATAM with the highest aquaculture production. The main objectives were to quantify the number of papers published between 2000 and 2023 on fish welfare by using scientific databases. A total of 285 papers were found for the period analysed. The country with the largest number of publications was Brazil (75.79%), followed by Chile (13.33%), Mexico (7.02%), Peru (1.75%), Ecuador, and Colombia (1.05%). Nile tilapia was the most studied species, appearing in 30.18% of the publications, with most of the studies mainly dealing with nutrition (32.28%). The growth of aquaculture is leading to joint efforts to generate knowledge on welfare issues, especially in poorly studied species with high production, to create policies that help minimize welfare risks. Given this, the insights generated by this review could be a useful addition to approaches investigating the trends and concepts of fish welfare in LATAM.

Opioid Medication Errors in Patients Followed by Home Palliative Care Support Teams in the Community of Madrid.

The presence of comorbidities and complex drug regimens makes palliative care patients more susceptible to opioid medication errors. Most of the studies conducted so far have mainly focused on patients admitted to hospitals or hospice facilities. During this study, we examined the frequency of medication errors with opioids and the causes and consequences for patients, followed by home palliative care teams. Errors occurred in 39% of patients (n = 378) and 27% of all prescribed opioids (n = 708). Of the 148 (39%) patients with error/s in the opioid/s prescribed, in 55% the patient and/or the caregiver were involved in the error; in 26% the health care providers were involved. An association was found between the presence of error in the prescribed opioid and the level of patient education, p = .038, and with the number of days of follow-up, p < .001. Considering their formulation, the prescribed opioids were associated with medication error, type of error, and cause of the error. The study demonstrated an association between the route of administration and error p < .004, and type of error p < .001.

Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10.

Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.

Reporting guidelines for precision medicine research of clinical relevance: the BePRECISE checklist.

Precision medicine should aspire to reduce error and improve accuracy in medical and health recommendations by comparison with contemporary practice, while maintaining safety and cost-effectiveness. The etiology, clinical manifestation and prognosis of diseases such as obesity, diabetes, cardiovascular disease, kidney disease and fatty liver disease are heterogeneous. Without standardized reporting, this heterogeneity, combined with the diversity of research tools used in precision medicine studies, makes comparisons across studies and implementation of the findings challenging. Specific recommendations for reporting precision medicine research do not currently exist. The BePRECISE (Better Precision-data Reporting of Evidence from Clinical Intervention Studies & Epidemiology) consortium, comprising 23 experts in precision medicine, cardiometabolic diseases, statistics, editorial and lived experience, conducted a scoping review and participated in a modified Delphi and nominal group technique process to develop guidelines for reporting precision medicine research. The BePRECISE checklist comprises 23 items organized into 5 sections that align with typical sections of a scientific publication. A specific section about health equity serves to encourage precision medicine research to be inclusive of individuals and communities that are traditionally under-represented in clinical research and/or underserved by health systems. Adoption of BePRECISE by investigators, reviewers and editors will facilitate and accelerate equitable clinical implementation of precision medicine.

Needs assessment for creation of a platform trial network in metabolic-dysfunction associated steatohepatitis.

BACKGROUND: The EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project (IMI2-853966) aimed to develop tools to establish integrated research platforms (IRP) for conducting adaptive-design trials in various diseases, including metabolic-dysfunction associated steatohepatitis (MASH). One essential component of a successful MASH IRP is a robust and reliable Clinical Research Network (CRN). Herein, we outline the required elements and anticipated steps to set-up such a CRN. METHODS: We identified European clinical research sites that could potentially serve as the foundation for MASH IRP and a CRN. A survey was sent to sites to assess their interest in joining a CRN, their familiarity with platform trials, and their capacity to participate in a future MASH IRP. RESULTS: A total of 141 investigators were invited to participate in the survey, and 40% responded. More than half of the answers (52%) identify MASH with advanced fibrosis (F3-4) as the subpopulation with the greatest unmet need. Regarding the difficulty in identifying candidates for trials, 65% find it is moderately difficult and 30% very difficult. Most respondents (94%) believe that a platform trial could offer substantial benefits to patients. Nearly all researchers express interest in participating in a platform trial (78%), with 22% indicating their interest would be contingent on initial industry funding. CONCLUSION: While preliminary, our findings on responding sites are encouraging for the potential establishment of a CRN for a MASH IRP. However, funding schemes and sustainability strategies to provide proof-of-platform in MASH seem key in the short-term scenario.

Metabolic dysfunction-associated steatohepatitis (MASH) occurs when the liver becomes damaged due to the build up of fat, which is often related to obesity and diabetes. There is a lack of effective drug treatments for MASH, so strategies to strengthen clinical research in this area are needed. Here, we survey key European experts on MASH to assess their interest in joining a network of MASH researchers and their interest in participating in a new type of clinical trial called a platform trial, where multiple drugs can be tested simultaneously. Researchers largely agree that these are promising approaches to boost drug development in the field, although have concerns regarding funding and sustainability strategies. Our findings may inform the creation of a network of MASH researchers capable of running a platform trial, which in turn may speed up research into treatments for MASH.

Adverse Effects Related to Paediatric Influenza Vaccination and Its Influence on Vaccination Acceptability. The FLUTETRA Study: A Survey Conducted in the Region of Murcia, Spain.

BACKGROUND: During the 2022-23 season, three autonomous communities recommended influenza vaccination for all children between 6 and 59 months. The objective is to evaluate the adverse effects associated with the administered influenza vaccines in the Region of Murcia, as well as their influence on the recommendation of the same to acquaintances or repetition in future seasons. MATERIAL AND METHODS: Cross-sectional descriptive study with an online questionnaire sent to the parents of vaccinated minors of 6-23 months of age receiving inactivated intramuscular vaccine (IIV) or 24-59 months of age receiving live-attenuated intranasal vaccine (LAIV). RESULTS: Among 4971 surveys received, the most common adverse effect for LAIV and IIV was runny nose (40.90%) and local pain (31.94%), respectively. Sixty percent of adverse effects lasted ≤ 1 day, and around 10% lasted ≥ 3 days. The interference of adverse effects with the minor's daily life was very infrequent (3.32%), as was the need for visiting the medical office (2.68%). Overall, 96.44% of parents would recommend influenza vaccination to friends and relatives after the experience. Only 3.56% would not recommend it, while 1.68% would not vaccinate their child against influenza again. The most frequently cited reason being adverse effects. CONCLUSIONS: Our study shows the safety of influenza vaccines. Despite the low impact of adverse effects, they influence some parents in their intention to continue vaccinating or recommending it to acquaintances, which remarks the need to reinforce the information given to parents so that this fact does not influence decision-making.

Three-year analysis of results, safety and progression in patients with open-angle glaucoma or ocular hypertension, undertaking trabecular microsurgery.

AIM: To evaluate the efficacy, safety, structural and functional progression following the insertion of iStent inject ® implants in patients with open-angle glaucoma or ocular hypertension at a tertiary-level hospital. MATERIALS AND METHODS: A retrospective study included 98 eyes (57 males and 41 females) with open-angle glaucoma or ocular hypertension, which underwent iStent inject W® implantation (Glaukos, Corporation, CA) between December 2018 and December 2022. Differences in intraocular pressure (IOP), the number of hypotensive eye drops used, and structural and functional tests were assessed between preoperative values and subsequent reviews during a follow-up period of one (n = 98), two (n = 55), and three years (n = 15) after surgery. RESULTS: Among the 98 eyes studied, 85% were diagnosed with open-angle glaucoma (50% mild, 32% moderate, and 18% severe) and 15% with ocular hypertension. There was a statistically significant reduction in IOP compared to preoperative values for all visits except the 1-month (p = 0.36) and 3-year (p = 0.39) visits. Visual acuity increased from 0.39 ± 0.25 to 0.72 ± 0.24 (p < 0.01), considering that a significant portion of the interventions included cataract surgery. Before surgery, 66% of the sample used 2 or more hypotensive medications. Post-surgery, the number of hypotensive medications decreased (from 1.88 ± 0.84 to 0.21 ± 0.59 at 3 years) (p < 0.01), with an 88.9% reduction in the number of medications over three years. After surgery, 75% of cases did not require any medication. Regarding structural and functional tests, thickness of retinal nerve fiber layers (RNFL (p = 0.35), excavation / papilla ratio E/P (p = 0.31), visual function index (VFI (p = 0.06), and deviation mean (MD (p = 0.06) showed no statistically significant differences post-intervention. However, standard deviation of the pattern (DSM) did exhibit differences, decreasing from 5.46 ± 4.03 dB to 5.34 ± 3.48 dB (p = 0.02). CONCLUSION: The results of this study suggest that the iStent inject W® technique constitutes an effective and safe option for tension control and glaucoma treatment.

Epidural Blood Patch for the Treatment of Spontaneous Intracranial Hypotension: A Case Series.

BACKGROUND: Epidural blood patch (EBP) is frequently used for the treatment of spontaneous intracranial hypotension (SIH) and anesthesiologists are often involved in performing such procedures. However, the optimal technique and approach of EBP remains uncertain. METHODS: This case series included adult patients with SIH who underwent EBPs at London Health Science Centre, Ontario, Canada between 2010 and 2022. Demographics, clinical presentations, investigations, and EBP treatment details were collected and analyzed. Univariate analysis was used to investigate the association of the variables with the likelihood of EBP 1-month efficacy and the efficacy duration of EBP. RESULTS: The study included 36 patients with SIH who received at least 1 EBP. EBPs provided immediate relief in almost all patients, albeit with diminishing effects over time. The 1-month efficacy improved with increasing number of EBP attempts (P=0.032, Fisher exact test), though no particular EBP technique or volume of injectate was associated with better efficacy (P=0.38, Fisher exact test). Though permanent resolution of symptoms was observed in only 24 of 82 EBPs (29%), 24 of 36 patients (67%) had permanent symptom resolution following repeated EBPs. CONCLUSIONS: EBP is a promising treatment and symptomatic relief option in patients suffering from the debilitating symptoms of SIH. Tailored EBP techniques, including use of targeted higher volume EBP and a multi-level catheter guided technique for refractory cases, showed efficacy in our institutional setting. Despite its limitations, this study contributes valuable insights and experiences into the use of EBP for treatment of SIH.

A produção sobre Ciência Aberta na área de Ciência da Informação no Brasil: análise no mapa temático das publicações da Brapci ­ 2015 a 2019 / The production on Open Science in the Information Science area in Brazil: analysis on the thematic map of Brapci publications ­ 2015 to 2019 / La producción sobre Ciencia Abierta en el área de Ciencias de la Información en Brasil: análisis sobre el mapa temático de las publicaciones de Brapci ­ 2015 a 2019

O texto discorre sobre relações entre a Ciência da Informação e o movimento da Ciência Aberta, sob a ótica de artigos científicos identificados na Base de Dados Referenciais de Artigos de Periódicos em Ciência da Informação. Objetiva determinar dimensões, campos e movimentos que se relacionam, estabelecendo um panorama dessa relação com as pesquisas brasileiras no período entre 2015 e 2019 no domínio da comunicação científica. A metodologia é a revisão narrativa de literatura, por meio da aplicação da análise de títulos, resumos e palavras-chave dos artigos selecionados. O campo empírico é composto pelos resultados obtidos pela busca na base, totalizando 36 resultados. Conclui-se que a Ciência da Informação está se relacionando com a Ciência Aberta, observando-se a prevalência de estudos sobre temáticas de dados de pesquisa abertos e sobre repositórios, de acordo com o período observado, como maneiras de aperfeiçoar os fazeres científicos.

The text discusses the relationship between Information Science and the Open Science movement, from the perspective of scientific articles identified in the Referential Database of Journal Articles in Information Science. The objective is to determine the dimensions, fields, and movements related, establishing an overview of this relationship with Brazilian research between 2015 and 2019, in the domain of scientific communication. The methodology employed is the narrative literature review, through the analysis of titles, abstracts, and keywords of selected articles. The empirical field consists of the results obtained through the search in the database, totaling 36 results. It is concluded that Information Science is relating to Open Science, with a prevalence of studies on open research data and repositories, according to the observed period, as ways to enhance scientific practices.

El texto discute la relación entre la Ciencia de la Información y el movimiento de la Ciencia Abierta, desde la perspectiva de artículos científicos identificados en la Base de Datos Referencial de Artículos de Revistas en Ciencia de la Información. El objetivo es determinar dimensiones, campos y movimientos relacionados, estableciendo una visión general de esta relación con la investigación brasileña entre 2015 y 2019, en el ámbito de la comunicación científica. La metodología es la revisión narrativa de literatura, a través del análisis de títulos, resúmenes y palabras clave de artículos seleccionados. El campo empírico consiste en los resultados obtenidos mediante la búsqueda en la base de datos, con 36 resultados. Se concluye que la Ciencia de la Información se relaciona con la Ciencia Abierta, con una prevalencia de estudios sobre datos de investigación abiertos y repositorios, según el período observado, como formas de mejorar las prácticas científicas.

A Novel Web-Based Application for Influenza and COVID-19 Outbreak Detection and Response in Residential Aged Care Facilities.

Unlabelled: The use of innovative digital health technologies in public health is expanding quickly, including the use of these tools in outbreak response. The translation of a digital health innovation into effective public health practice is a complex process requiring diverse enablers across the people, process, and technology domains. This paper describes a novel web-based application that was designed and implemented by a district-level public health authority to assist residential aged care facilities in influenza and COVID-19 outbreak detection and response. It discusses some of the challenges, enablers, and key lessons learned in designing and implementing such a novel application from the perspectives of the public health practitioners (the authors) that undertook this project.

Effects of Blood Flow Restriction Training in Patients before and after Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-Analysis.

(1) Objective: To examine the effects of blood flow restriction (BFR) training on muscle strength, cross-sectional area and knee-related function in patients selected for anterior cruciate ligament reconstruction (ACLR). (2) Methods: A literature search was conducted in PubMed, PEDro, Cochrane Library, Web of Science, SCOPUS, and ProQuest databases until 20 May 2024. Controlled clinical trials comparing the effects of BFR training with unrestricted training in patients before or after ACLR were selected. The GRADE approach was used to assess the degree of certainty for each meta-analysis. (3) Results: Ten studies were included (n = 287 participants). Standardized mean differences in favor of BFR training applied postoperatively were observed in knee extensor (SMD = 0.79; 95% CI = 0.06 to 1.52; I2: 68%) and flexor isokinetic strength (SMD = 0.53; 95% CI = 0.04 to 1.01; I2: 0%), and quadriceps cross-sectional area (SMD = 0.76; 95% CI = 0.27 to 1.26; I2: 0%). No changes were found in knee extensor isometric strength and knee-related function. The degree of certainty according to the GRADE was very low. (4) Conclusions: Very low degree of certainty suggests that BFR training provides additional benefits to unrestricted training on isokinetic strength and quadriceps cross-sectional area in patients undergoing ACLR.

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.

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.

The lipopolysaccharide-TLR4 axis regulates hepatic glutaminase 1 expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.

INTRODUCTION: Ammonia is a pathogenic factor implicated in the progression of metabolic-associated steatotic liver disease (MASLD). The contribution of the glutaminase 1 (GLS) isoform, an enzyme converting glutamine to glutamate and ammonia, to hepatic ammonia build-up and the mechanisms underlying its upregulation in metabolic-associated steatohepatitis (MASH) remain elusive. METHODS: Multiplex transcriptomics and targeted metabolomics analysis of liver biopsies in dietary mouse models representing the whole spectra of MASLD were carried out to characterize the relevance of hepatic GLS during disease pathological progression. In addition, the acute effect of liver-specific GLS inhibition in hepatic ammonia content was evaluated in cultured hepatocytes and in in vivo mouse models of diet-induced MASLD. Finally, the regulatory mechanisms of hepatic GLS overexpression related to the lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4) axis were explored in the context of MASH. RESULTS: In mouse models of diet-induced MASLD, we found that augmented liver GLS expression is closely associated with the build-up of hepatic ammonia as the disease progresses from steatosis to steatohepatitis. Importantly, the acute silencing/pharmacological inhibition of GLS diminishes the ammonia burden in cultured primary mouse hepatocytes undergoing dedifferentiation, in steatotic hepatocytes, and in a mouse model of diet-induced steatohepatitis, irrespective of changes in ureagenesis and gut permeability. Under these conditions, GLS upregulation in the liver correlates positively with the hepatic expression of TLR4 that recognizes LPS. In agreement, the pharmacological inhibition of TLR4 reduces GLS and hepatic ammonia content in LPS-stimulated mouse hepatocytes and hyperammonemia animal models of endotoxemia. CONCLUSIONS: Overall, our results suggest that the LPS/TLR4 axis regulates hepatic GLS expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.