Search Results (25)

Background/Objectives: The study aims to identify key cognitive and non-cognitive variables (e.g., clinical, neuroimaging, and genetic data) predicting cognitive decline in Parkinson’s disease (PD) patients using machine learning applied to a sample (N = 618) from the Parkinson’s Progression Markers Initiative database. Traditional research has mainly employed explanatory approaches to explore variable relationships, rather than maximizing predictive accuracy for future cognitive decline. In the present study, we implemented a predictive framework that integrates a broad range of baseline cognitive, clinical, genetic, and imaging data to accurately forecast changes in cognitive functioning in PD patients. Methods: An artificial neural network was trained on baseline data to predict general cognitive status three years later. Model performance was evaluated using 5-fold stratified cross-validation. We investigated model interpretability using explainable artificial intelligence techniques, including Shapley Additive Explanations (SHAP) values, Group-Wise Feature Masking, and Brute-Force Combinatorial Masking, to identify the most influential predictors of cognitive decline. Results: The model achieved a recall of 0.91 for identifying patients who developed cognitive decline, with an overall classification accuracy of 0.79. All applied explainability techniques consistently highlighted baseline MoCA scores, memory performance, the motor examination score (MDS-UPDRS Part III), and anxiety as the most predictive features. Conclusions: From a clinical perspective, the findings can support the early detection of PD patients who are more prone to developing cognitive decline, thereby helping to prevent cognitive impairments by designing specific treatments. This can improve the quality of life for patients and caregivers, supporting patient autonomy. Full article

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease that has emerged as a significant cause of heart failure. Advances in the understanding of ATTR-CM pathophysiology have revolutionised its therapeutic landscape over the past decade, with the development of targeted therapies that are able to improve survival and quality of life. TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation. Clinical trials have demonstrated their efficacy both in improving survival and quality of life in patients with ATTR-CM. Gene-silencing therapies using small interfering RNAs (siRNAs), such as patisiran and vutrisiran, or antisense oligonucleotide inhibitors (ASOs), such as inotersen and eplontersen, serve as powerful therapeutic options by decreasing TTR production; trials on patients with ATTR-CM have been recently published or are ongoing. Novel, emerging therapies aim to enhance fibril clearance using monoclonal antibodies, such as NI006, that target amyloid deposits in the myocardium, promoting their depletion, plausibly with regression of the structural and functional impairments caused by the disease. Concurrently, advancements in diagnostic modalities have facilitated earlier detection of this disease, allowing the timely initiation of treatment with a more significant impact on patients’ survival and quality of life. Despite these strides, challenges remain, including the high cost of disease-modifying therapy and the need for response criteria to monitor treatment’s efficacy. Future directions will involve improving patients’ screening to achieve earlier diagnoses, optimising patients’ selection for disease-modifying therapy and identifying criteria for the treatment’s response or lack thereof to possibly consider therapy switch or associations. In this review, we will explore the more recent therapeutic advancements in ATTR-CM, starting from traditional heart failure therapies and moving to disease-modifying therapies with a detailed evaluation of the registration trials to explore the strengths and shortcomings of each treatment. Full article

The identification of fungal pathogens in formalin-fixed paraffin-embedded (FFPE) tissues is an unmet need in human and animal medicine, and sequence-agnostic approaches are needed to identify emerging pathogens. Eleven FFPE biopsy specimens with etiologic diagnoses of fungal disease based on standard testing of paired fresh tissue samples were utilized here to evaluate metabarcoding approaches. The cases included tissues from three dogs, three cats, one box turtle, one goat, one common loon, and one gray tree frog. The diagnoses from the fresh tissues in these cases were Microsporum canis, Penicillium sp., Exophiala sp. (likely E. jeanselmei), Verticillium sp., Rhizopus sp., atypical Cryptococcus neoformans, Conidiobolus spp., Aspergillus fumigatus, Cryptococcus neoformans var grubii, Batrachochytrium dendrobatidis, Fusarium solani, Blastomyces dermatitidis, Coccidiodes immitis, and Histoplasma capsulatum. We compared the ITS1 and 28S D1 rRNA gene genetic markers in combination with several bioinformatic strategies to identify fungal pathogens in the FFPE tissue samples, with a success rate of 9/11. These methods could allow diagnosticians who receive only FFPE tissues and see fungal pathogens to speciate the pathogens and could be of value in retrospective studies wherein FFPE tissue is the only archived tissue. Furthermore, these techniques could be of use to researchers investigating polymicrobial communities where DNA preservation is suboptimal. Full article

Ablative materials are widely employed to protect space vehicles from the extreme thermal conditions experienced during their flight into a planetary atmosphere. Carbon-phenolic ablators are composed of a phenolic matrix and a fibrous carbon reinforcement. In the present study, the fibrous reinforcement has been modified through the deposition of thin protective layers of zirconium oxide and aluminum oxide, with the objective of reducing fiber recession and oxidation. The depositions were carried out via atomic layer deposition (ALD), a method that allows for the controlled deposition of uniform and conformal coatings on the carbon felt fibers. The depositions were subsequently evaluated through SEM-EDS analysis. Pristine and ALD-modified felts were impregnated with a phenolic resin matrix and the ablation performance of the composite materials was evaluated through oxyacetylene flame tests. The results demonstrated that, in comparison to uncoated ablators, the ALD-modified samples exhibited enhanced performance in terms of mass loss and surface recession: compared to uncoated ablators, the former was 14% lower and the latter was diminished by 50%. Moreover, the morphological characterization of the tested specimens revealed a significantly reduced degree of oxidation of the coated fibers which were directly exposed to the flame. Full article

Research has highlighted racial and socioeconomic disparities for families in child welfare, with calls to address inequities through trainings and structural change. However, few measures have been developed to assess the recognition of racial and class biases among child welfare practitioners, one key step in addressing implicit biases and reducing racial disparities. While the Families First Prevention Services Act has prioritized evidence-based practices, it is crucial to ensure that practitioners are culturally responsive. This study developed and piloted the Race and Class Bias in Child Welfare Scale to measure the awareness of implicit and structural biases among child welfare practitioners. The development and validation of the Race and Class Bias in Child Welfare Scale included three parts: (1) scale development; (2) scale piloting using exploratory factor analysis; and (3) scale validation using confirmatory factor analysis. Two main factors were identified that explained 68.05% of the total variance; eight of the nine items loaded onto the two factors. Items on the first factor reflected implicit bias recognition, and items on the second factor reflected structural bias. Preliminary findings suggest that a two-factor scale presents good internal reliability and validity. As the Family First Preservation Services Act continues to prioritize evidence-based practices, it is important to consider the cultural sensitivity and responsiveness of providers administering them. Full article

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients treated with EGFR–tyrosine kinase inhibitors (TKIs) inevitably develop resistance through several biological mechanisms. However, little is known on the molecular mechanisms underlying acquired resistance to suboptimal EGFR-TKI doses, due to pharmacodynamics leading to inadequate drug exposure. To evaluate the effects of suboptimal EGFR-TKI exposure on resistance in NSCLC, we obtained HCC827 and PC9 cell lines resistant to suboptimal fixed and intermittent doses of gefitinib and compared them to cells exposed to higher doses of the drug. We analyzed the differences in terms of EGFR signaling activation and the expression of epithelial–mesenchymal transition (EMT) markers, whole transcriptomes byRNA sequencing, and cell motility. We observed that the exposure to low doses of gefitinib more frequently induced a partial EMT associated with an induced migratory ability, and an enhanced transcription of cancer stem cell markers, particularly in the HCC827 gefitinib-resistant cells. Finally, the HCC827 gefitinib-resistant cells showed increased secretion of the EMT inducer transforming growth factor (TGF)-β1, whose inhibition was able to partially restore gefitinib sensitivity. These data provide evidence that different levels of exposure to EGFR-TKIs in tumor masses might promote different mechanisms of acquired resistance. Full article

Background/Objectives: Several studies have shown a relation between obesity and cognitive decline, highlighting a significant global health challenge. In recent years, artificial intelligence (AI) and machine learning (ML) have been integrated into clinical practice for analyzing datasets to identify new risk factors, build predictive models, and develop personalized interventions, thereby providing useful information to healthcare professionals. This systematic review aims to evaluate the potential of AI and ML techniques in addressing the relationship between obesity, its associated health consequences, and cognitive decline. Methods: Systematic searches were performed in PubMed, Cochrane, Web of Science, Scopus, Embase, and PsycInfo databases, which yielded eight studies. After reading the full text of the selected studies and applying predefined inclusion criteria, eight studies were included based on pertinence and relevance to the topic. Results: The findings underscore the utility of AI and ML in assessing risk and predicting cognitive decline in obese patients. Furthermore, these new technology models identified key risk factors and predictive biomarkers, paving the way for tailored prevention strategies and treatment plans. Conclusions: The early detection, prevention, and personalized interventions facilitated by these technologies can significantly reduce costs and time. Future research should assess ethical considerations, data privacy, and equitable access for all. Full article

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs. Full article

Crohn’s and ulcerative colitis are common conditions associated with inflammatory bowel disease as well as intestinal flora and epithelial barrier dysfunction. A novel fermented Lactobacillus brevis (AL0035) herein assayed in a trinitro benzene sulfonic acid (TNBS)-induced colitis mice model after oral administration significantly counteracted the body weight loss and improves the disease activity index and histological injury scores. AL0035 significantly decreased the mRNA and protein expression of different pro-inflammatory cytokines (TNFalpha, IL-1beta, IL-6, IL-12, IFN-gamma) and enhanced the expression of IL-10. In addition, the probiotic promoted the expression of tight junction proteins, such as ZO-1, keeping the intestinal mucosal barrier function to attenuate colitis symptoms in mice. Markers of inflammation cascade such as myeloperoxidase (MPO) and PPAR-gamma measured in the colon were also modified by AL0035 treatment. AL0035 was also able to reduce different lymphocyte markers’ infiltration in the colon (GATA-3, T-Bet, NK1.1) and monocyte chemoattractant protein-1 (MCP-1/CCL2), a key chemokine involved in the migration and infiltration of monocytes/macrophages in the immunological surveillance of tissues and inflammation. In colonic microbiota profile analysis through 16S rRNA sequencing, AL0035 increased the microbial diversity depleted by TNBS administration and the relative abundance of the Lactobacillaceae and Lachnospiraceae families, whereas it decreased the abundance of Proteobacteria. Altogether, these data indicated that AL0035 could lower the severity of colitis induced by TNBS by regulating inflammatory cytokines, increasing the expression of tight junction proteins and modulating intestinal microbiota, thus preventing tissue damage induced by colitis. Full article

The COVID-19 pandemic, once a global crisis, is now largely under control, a testament to the extraordinary global efforts involving vaccination and public health measures. However, the relentless evolution of SARS-CoV-2, leading to the emergence of new variants, continues to underscore the importance of remaining vigilant and adaptable. Monoclonal antibodies (mAbs) have stood out as a powerful and immediate therapeutic response to COVID-19. Despite the success of mAbs, the evolution of SARS-CoV-2 continues to pose challenges and the available antibodies are no longer effective. New variants require the ongoing development of effective antibodies. In the present study, we describe the generation and characterization of neutralizing mAbs against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein by combining plasmid DNA and recombinant protein vaccination. By integrating genetic immunization for rapid antibody production and the potent immune stimulation enabled by protein vaccination, we produced a rich pool of antibodies, each with unique binding and neutralizing specificities, tested with the ELISA, BLI and FACS assays and the pseudovirus assay, respectively. Here, we present a panel of mAbs effective against the SARS-CoV-2 variants up to Omicron BA.1 and BA.5, with the flexibility to target emerging variants. This approach ensures the preparedness principle is in place to address SARS-CoV-2 actual and future infections. Full article

SiC/SiC ceramic matrix composites (SiCf/SiC CMCs) are regarded as the new materials for the hot-section components of aircraft gas turbine engines, since they have one-third of the density of metallic superalloys, a higher temperature capability, good mechanical strength, and excellent thermal shock resistance. However, high-temperature water-vapor-rich combustion gases can induce severe surface recession phenomena in SiC/SiC leading to component failure. For this reason, it is necessary to design protective coatings, i.e., environmental barrier coatings (EBCs), able to protect the SiC/SiC surface in combustion environments. In the present work, ytterbium monosilicate (Yb₂SiO₅), stable when exposed to water vapor at high temperatures, and ytterbium disilicate (Yb₂Si₂O₇), characterized by a thermal expansion coefficient closer to that of the substrate, were selected for a multilayer EBC system. EBCs were processed using the atmospheric plasma spray (APS) technique. A set of deposition parameters were tested, varying the power of the torch, and the composition and microstructure of the deposited coatings were studied in terms of porosity, crack density, and post-deposition phase retention by performing SEM, EDS, and XRD analysis. The results allow for the definition of the influence of deposition parameters on the final properties of multilayer EBC coatings. Full article

A new lead-free electroless Ni-P plating solution was developed for the deposition of coatings with medium phosphorus content (MP, 6–9 wt%), and its composition was optimized to obtain deposits with high phosphorus (HP, 10–14 wt%). Cleaning and activation treatments were studied in terms of effectiveness and influence on the deposition rate. The concentration of reagents (nickel salt, complexing agent, reducing agent and stabilizer) was studied, and their combined effect on P content and plating rate was investigated. The obtained coatings were analyzed by SEM and XRD and thermally treated at 400 °C and 600 °C to study microstructural evolution. Vickers hardness was measured on as-deposited and annealed coatings to relate hardness evolution to microstructural changes after thermal treatments. Optimal deposition conditions were determined, enabling the production of MP coatings (6.5 wt% P) with a plating rate of 40 µm/h and HP coatings (10.9 wt% P) with a plating rate of 25 µm/h at 90 °C. Samples heat-treated at 400 °C showed improved hardness thanks to crystallization and microprecipitation of Ni₃P hard phases, whereas hardness decrease was observed after treatment at 600 °C due to the combined effect of grain growth and coarsening of Ni₃P precipitates. No through-the-thickness cracks were detected by the Ferroxyl reagent after heat treatments. Full article

Acute myocardial edema (AME) is increased water content in the myocardium and represents the first and transient pathophysiological response to an acute myocardial injury. In-vivo and non-invasive evaluation is feasible with cardiac magnetic resonance (CMR), which is a powerful imaging technique capable of tissue characterization. In the clinical setting, early demonstration of AME has a recognized diagnostic value for acute coronary syndromes and acute myocarditis, although its prognostic value is not well established. This article provides a comprehensive narrative review on the clinical meaning of AME in heart diseases. In particular, the available evidence of a possible favourable prognostic value in several clinical scenarios is addressed. Full article

Orodispersible film (ODF) is an innovative dosage form used to administer drugs and nutrients, designed to disintegrate or dissolve in the oral cavity without needing water. One of the advantages of ODF is that it is suitable for administration in older people and children who have difficulty swallowing because of psychological or physiological deficiencies. This article describes the development of an ODF based on maltodextrin, which is easy to administer, has a pleasant taste, and is suitable for iron supplementation. An ODF containing 30 mg of iron as pyrophosphate and 400 µg of folic acid (iron ODF) was developed and manufactured on an industrial scale. The kinetic profile for serum iron and folic acid upon consumption of ODF compared with a Sucrosomial^® iron capsule (known for its high bioavailability) was evaluated in a crossover clinical trial. The study was conducted in nine healthy women, and the serum iron profile (AUC_0–8, T_max, and C_max) of both formulations was defined. Results showed that the rate and extent of elemental iron absorption with iron ODF was comparable to that obtained using the Sucrosomial^® iron capsule. These data represent the first evidence of iron and folic acid absorption concerning the newly developed ODF. Iron ODF was proven to be a suitable product for oral iron supplementation. Full article

Pulmonary arterial hypertension (PAH) is a life-threatening complication of connective tissue diseases (CTDs) characterised by increased pulmonary arterial pressure and pulmonary vascular resistance. CTD-PAH is the result of a complex interplay among endothelial dysfunction and vascular remodelling, autoimmunity and inflammatory changes, ultimately leading to right heart dysfunction and failure. Due to the non-specific nature of the early symptoms and the lack of consensus on screening strategies—except for systemic sclerosis, with a yearly transthoracic echocardiography as recommended—CTD-PAH is often diagnosed at an advanced stage, when the pulmonary vessels are irreversibly damaged. According to the current guidelines, right heart catheterisation is the gold standard for the diagnosis of PAH; however, this technique is invasive, and may not be available in non-referral centres. Hence, there is a need for non-invasive tools to improve the early diagnosis and disease monitoring of CTD-PAH. Novel serum biomarkers may be an effective solution to this issue, as their detection is non-invasive, has a low cost and is reproducible. Our review aims to describe some of the most promising circulating biomarkers of CTD-PAH, classified according to their role in the pathophysiology of the disease. Full article