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The case report shows the safety and efficacy of insulin treatment with Advanced Hybrid Closed Loop (AHCL) system in a young patient affected by permanent neonatal diabetes mellitus (PNDM) due to chromosome 8 deletion syndrome involving the GATA4 gene. In the first days of life, he presented hyperglycaemia and started an intravenous insulin infusion therapy, replaced by a continuous subcutaneous insulin infusion (CSII) with Medtronic Minimed 780G® insulin pump (Medtronic, Northridge, CA, USA). At the age of 2 years, the off-label activation of SmartGuard® automated insulin delivery mode led to a great improvement in glycaemic control, reaching all recommended targets. At the 1-month follow-up visit, Time in Range (TIR) increased from 66% to 79%, with a Time in Tight Range (TTIR) of 55% and a reduction of 11% in time in hyperglycaemia and of 2% in time in hypoglycaemia. During the entire follow-up, no episodes of ketoacidosis or severe hypoglycaemia were observed and the patient maintained the glycaemic recommended targets reached at 1 month. Maintaining optimal glycaemic control and reducing hyperglycaemia are essential for brain growth and neurocognitive development in young patients. AHCL use should be considered to ensure good glycaemic control in patients affected by neonatal diabetes. [ABSTRACT FROM AUTHOR]

While the number of publications on wine and health is steadily increasing, ranging from a molecular level to epidemiological studies, often with contradictory results, little attention has been given to a holistic approach to research, starting from the molecular level to arrive at pharmacological and medical conclusions. In this review, some unusual concepts are considered, such as the phytocomplex, the vehicle, and the Matrix effect. The concept of the phytocomplex is discussed, specifically the biological activities of Tyrosol, Hydroxytyrosol, and Resveratrol; indeed, the interactions among different molecules in herbal matrices provide a specific response. This is often markedly different from the response evoked by single constituents in the modulation of microbial populations in the gut, in intestinal stability and bioaccessibility, and, obviously, in inducing biological responses. Among the many alcoholic beverages which contain these molecules, wine has the most peculiar Matrix effect, which can heavily influence the bioavailability of the phytocomplex obtained by the fermentation processes that produce this beverage. Wine's Matrix effect plays an instrumental role in improving the beneficial compounds' bioavailability and/or in inhibiting alcohol metabolites' carcinogenicity. Underestimation of the wine Matrix effect could lead to deceiving results, as in the case of dealcoholized wine or wine-compound-based nutritional supplements; alternatively, this can occur in the emphasis of a single component's toxic activity, in this case, alcohol, ignoring the specific molecular-level protective action of other compounds (polyphenols) that are present in the same matrix. The dark side of the Matrix effect is also discussed. This review confirms the research recommendations made by the WHO Scientific Group, which suggests it is important "to investigate the possible protective effects of ingredients other than alcohol in alcoholic beverages", considering that most recent studies seem not only relevant but also capable of directing future research towards innovative points of view that have so far been too neglected. [ABSTRACT FROM AUTHOR]

Consuming an unbalanced diet and being overweight represent a global health problem in young people and adults of both sexes, and may lead to metabolic syndrome. The diet-induced obesity (DIO) model in the C57BL/6J mouse substrain that mimics the gradual weight gain in humans consuming a "Western-type" (WD) diet is of great interest. This study aims to characterize this animal model, using high-frequency ultrasound imaging (HFUS) as a complementary tool to longitudinally monitor changes in the liver, heart and kidney. Long-term WD feeding increased mice body weight (BW), liver/BW ratio and body condition score (BCS), transaminases, glucose and insulin, and caused dyslipidemia and insulin resistance. Echocardiography revealed subtle cardiac remodeling in WD-fed mice, highlighting a significant age–diet interaction for some left ventricular morphofunctional parameters. Qualitative and parametric HFUS analyses of the liver in WD-fed mice showed a progressive increase in echogenicity and echotexture heterogeneity, and equal or higher brightness of the renal cortex. Furthermore, renal circulation was impaired in WD-fed female mice. The ultrasound and histopathological findings were concordant. Overall, HFUS can improve the translational value of preclinical DIO models through an integrated approach with conventional methods, enabling a comprehensive identification of early stages of diseases in vivo and non-invasively, according to the 3Rs. [ABSTRACT FROM AUTHOR]

Background: Biparametric MRI (bpMRI) has an important role in the diagnosis of prostate cancer (PCa), by reducing the cost and duration of the procedure and adverse reactions. We assess the additional benefit of the ADC map in detecting prostate cancer (PCa). Additionally, we examine whether the ADC value correlates with the presence of clinically significant tumors (csPCa). Methods: 104 peripheral lesions classified as PI-RADS v2.1 score 3 or 3+1 at the mpMRI underwent transperineal MRI/US fusion-guided targeted biopsy. Results: The lesions were classified as PI-RADS 3 or 3+1; at histopathology, 30 were adenocarcinomas, 21 of which were classified as csPCa. The ADC threshold that maximized the Youden index in order to predict the presence of a tumor was 1103 (95% CI (990, 1243)), with a sensitivity of 0.8 and a specificity of 0.59; both values were greater than those found using the contrast medium, which were 0.5 and 0.54, respectively. Similar results were also found with csPCa, where the optimal ADC threshold was 1096 (95% CI (988, 1096)), with a sensitivity of 0.86 and specificity of 0.59, compared to 0.49 and 0.59 observed in the mpMRI. Conclusions: Our study confirms the possible use of a quantitative parameter (ADC value) in the risk stratification of csPCa, by reducing the number of biopsies and, therefore, the number of unwarranted diagnoses of PCa and the risk of overtreatment. [ABSTRACT FROM AUTHOR]

Satellite remote sensing is currently an established, effective, and constantly used tool and methodology for monitoring agriculture and fertilisation. At the same time, in recent years, the need for the detection of livestock manure and digestate spreading on the soil is emerging, and the development of spectral indices and classification processes based on satellite multispectral data acquisitions is growing. However, the application of such indicators is still underutilised and, given the polluting impact of livestock manure and digestate on soil, groundwater, and air, an in-depth study is needed to improve the monitoring of this practice. Additionally, this paper aims at exposing a new spectral index capable of detecting the land affected by livestock manure and digestate spreading. This indicator was created by studying the spectral response of bare soil and livestock manure and digestate, using Copernicus Sentinel-2 MSI satellite acquisitions and ancillary datasets (e.g., soil moisture, precipitation, regional thematic maps). In particular, time series of multispectral satellite acquisitions and ancillary data were analysed, covering a survey period of 13 months between February 2022 and February 2023. As no previous indications on fertilisation practices are available, the proposed approach consists of investigating a broad-spectrum area, without investigations of specific test sites. A large area of approximately 236,344 hectares covering three provinces of the Emilia-Romagna Region (Italy) was therefore examined. A series of ground truth points were also collected for assessing accuracy by filling in the confusion matrix. Based on the definition of the spectral index, a value of the latter greater than three provides the most conservative threshold for detecting livestock manure and digestate spreading with an accuracy of 62.53%. Such results are robust to variations in the spectral response of the soil. On the basis of these very encouraging results, it is considered plausible that the proposed index could improve the techniques for detecting the spreading of livestock manure and digestate on bare ground, classifying the areas themselves with a notable saving of energy compared to the current investigation methodologies directly on the ground. [ABSTRACT FROM AUTHOR]

Pulmonary vasculitis identifies a heterogeneous group of diseases characterized by inflammation, damage and necrosis of the wall of pulmonary vessels. The most common approach to classify vasculitis is according to etiology, therefore dividing them into primary and secondary, with a further sub-classification of primary vasculitis based on the size of the affected vessels (large, medium, and small). Pulmonary involvement is frequently observed in patients with systemic vasculitis and radiological presentation is not pathognomonic, but may vary between diseases. The main findings using high-resolution computed tomography (HRCT) include small vessel wall thickening, nodular lesions, cavitary lesions, reticular opacities, ground-glass opacities (GGO), consolidations, interlobular septal thickening, tracheobronchial stenosis, and aneurysmal dilatation of pulmonary arteries, with or without pleural effusion. Radiological diagnosis alone is difficult since signs and symptoms of lung vessel involvement are often non-specific and might overlap with other conditions such as infections, connective tissue diseases and neoplasms. Therefore, the aim of this review is to describe the most common radiological features of lung involvement in pulmonary vasculitis so that, alongside detailed clinical history and laboratory tests, a prompt diagnosis can be performed. [ABSTRACT FROM AUTHOR]

The iminosugar 1-deoxynojirimicyn (DNJ) contained in mulberry leaves has displayed systemic beneficial effects against disorders of carbohydrate metabolism. Nevertheless, its effect is impaired by the short half-life. Alginate-based carriers were developed to encapsulate a DNJ-rich mulberry extract: Ca-alginate beads, obtained by external gelation, and spray-dried alginate microparticles (SDMs). Mean size and distribution, morphology, drug loading, encapsulation efficiency, experimental yield, and release characteristics were determined for the two formulations. Ca-alginate beads and SDMs exhibited an encapsulation efficiency of about 54% and 98%, respectively, and a DNJ loading in the range of 0.43–0.63 μg/mg. The in vitro release study demonstrated the carriers' capability in controlling the DNJ release in acid and basic conditions (<50% in 5 h), due to electrostatic interactions, which were demonstrated by 1H-NMR relaxometry studies. Thus, alginate-based particles proved to be promising strategies for producing food supplements containing mulberry leaf extracts for the management of hyperglycemic state. [ABSTRACT FROM AUTHOR]

Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod–cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5–10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants. [ABSTRACT FROM AUTHOR]

Background: Actinomycosis represents a challenging and under-reported complication of vascular surgery. Optimal management of Actinomyces spp. prosthetic vascular graft infection (PVGI) is highly uncertain because of the paucity of reports on this disease. Methods: We conducted a retrospective case-series of Actinomyces-PVGI that occurred in the last five years in two major university hospitals in northern Italy. We searched for previously published cases in the scientific literature. Results: We report five original cases of Actinomyces spp. prosthetic vascular graft infection following aortic aneurysm repair. Our literature review retrieved eight similar cases. Most patients were immunocompetent males. Most infections were polymicrobial (11/13 cases), with a prevalence of A. odontolyticus involvement (3/13 cases were associated with. Salmonella spp. infection). All cases had a late presentation (≥4 months from graft placement), with 61% associated with an aorto-enteric fistula. All patients received antibiotic therapy, but the duration was highly heterogeneous (from two weeks to life-long antibiotics). The patients without surgical revision experienced septic recurrences (2/13), permanent dysfunction (1/13), or a fatal outcome (2/13), while of the remainder who underwent vascular graft explant, six recovered completely and one developed a periprosthetic abscess. In two cases follow-up was not available. Conclusions: This case-series aims to raise the diagnostic suspicion and to describe the current management of Actinomyces-PVGIs. We highlight a high heterogeneity in antibiotic duration, choice of the antibiotic regimen, and surgical management. Higher reporting rate is advisable to produce better evidence and optimize management of this rare complication of vascular surgery. [ABSTRACT FROM AUTHOR]

Novel Food is a new category of food, regulated by the European Union Directive No. 2015/2283. This latter norm defines a food as "Novel" if it was not used "for human consumption to a significant degree within the Union before the date of entry into force of that regulation, namely 15 May 1997". Recently, Novel Foods have received increased interest from researchers worldwide. In this sense, the key areas of interest are the discovery of new benefits for human health and the exploitation of these novel sources of materials in new fields of application. An emerging area in the pharmaceutical and medicinal fields is nanotechnology, which deals with the development of new delivery systems at a nanometric scale. In this context, this review aims to summarize the recent advances on the design and characterization of nanodelivery systems based on materials belonging to the Novel Food list, as well as on nanoceutical products formulated for delivering compounds derived from Novel Foods. Additionally, the safety hazard of using nanoparticles in food products, i.e., food supplements, has been discussed in view of the current European regulation, which considers nanomaterials as Novel Foods. [ABSTRACT FROM AUTHOR]

Livestock manure management, especially related to soil-fertilisation practice, is responsible for most of the emissions in agriculture, and in particular the ammonia emissions (NH3), which play a key role in environmental problems, affecting water, soil and air quality. Within the digital agricultural framework, EO data contribute to agricultural-practices monitoring such as manure spreading, to mitigate pollutant emissions. This study presents a GIS-based tool on an open-source platform, developed for susceptibility estimation of sewage spreading occurrence in agricultural areas of Italy. The tool is based on the analysis of multispectral and hyperspectral satellite time series in synergy with field data and ancillary information collected from regional repositories, to produce a series of classified and prioritised spatially explicit information. Spectral analysis of satellite acquisitions enabled the identification of manure spreading with the precision of about 83%. Field campaigns from October to March were carried out to validate the spreading event. The case study demonstrates the ability of the proposed GIS-based tool in supporting the monitoring of manure spreading. [ABSTRACT FROM AUTHOR]

In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. We hypothesize that both circulating and neuroimaging-based markers might improve the prediction of bleeding and thrombotic risk in anticoagulated AF patients. The Strat-AF study is an observational, prospective, single-center study enrolling 170 patients with AF; recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging and circulating biomarkers assessment. The main outcome is the evaluation of cerebral microangiopathy related to the levels of circulating biomarkers of inflammation and extracellular matrix (ECM) remodeling. At multivariate logistic regression analysis adjusted for age, sex, CHA2DS2-VASc, HAS-BLED and type of anticoagulant, matrix metalloproteinases (MMP)-2 levels were significantly and positively associated with the presence of cerebral microbleeds (CMBs). A significant association between MMP-2, tissue inhibitor of metalloproteinases (TIMP)-1,-2,-4 levels and white matter hyperintensity was also found. Concerning the small vessel disease (SVD) score, MMP-2 and TIMP-1,-2 levels were associated with the presence of two and three or more signs of SVD, whereas TIMP-4 levels were associated with the presence of three signs of SVD with respect to patients with no instrumental signs of SVD. As regarding the presence of enlarged perivascular spaces (EPVS), a significant association was found for high levels of interleukin (IL)-8 and TIMP 1-2-3. These results demonstrate that patients with AF have evidence of impaired ECM degradation, which is an independent risk factor for thrombotic complications of AF patients on oral anticoagulant therapy. The incorporation of these markers in the prognostic schemes might improve their clinical capability in predicting stroke risk and thrombotic complications. [ABSTRACT FROM AUTHOR]

The vaccination campaign against SARS-CoV-2 relies on the world-wide availability of effective vaccines, with a potential need of 20 billion vaccine doses to fully vaccinate the world population. To reach this goal, the manufacturing and logistic processes should be affordable to all countries, irrespective of economical and climatic conditions. Outer membrane vesicles (OMVs) are bacterial-derived vesicles that can be engineered to incorporate heterologous antigens. Given the inherent adjuvanticity, such modified OMVs can be used as vaccines to induce potent immune responses against the associated proteins. Here, we show that OMVs engineered to incorporate peptides derived from the receptor binding motif (RBM) of the spike protein from SARS-CoV-2 elicit an effective immune response in vaccinated mice, resulting in the production of neutralizing antibodies (nAbs) with a titre higher than 1:300. The immunity induced by the vaccine is sufficient to protect the animals from intranasal challenge with SARS-CoV-2, preventing both virus replication in the lungs and the pathology associated with virus infection. Furthermore, we show that OMVs can be effectively decorated with the RBM of the Omicron BA.1 variant and that such engineered OMVs induce nAbs against Omicron BA.1 and BA.5, as measured using the pseudovirus neutralization infectivity assay. Importantly, we show that the RBM438–509 ancestral-OMVs elicited antibodies which efficiently neutralize in vitro both the homologous ancestral strain, the Omicron BA.1 and BA.5 variants with a neutralization titre ranging from 1:100 to 1:1500, suggesting its potential use as a vaccine targeting diverse SARS-CoV-2 variants. Altogether, given the convenience associated with the ease of engineering, production and distribution, our results demonstrate that OMV-based SARS-CoV-2 vaccines can be a crucial addition to the vaccines currently available. [ABSTRACT FROM AUTHOR]

Asthma is the most frequent chronic disease of childhood, affecting up to 20% of children worldwide. The main guidelines on asthma maintenance therapy in pediatrics suggest different approaches and describe different stages of asthma to determine the most appropriate treatment. This project aims to summarize the most recent evidence regarding maintenance therapy for asthma in children and adolescents. A multidisciplinary panel of experts was asked clinical questions regarding the treatment of children and adolescents with asthma. Overall, 10 clinical questions were addressed, and the search strategy included accessing electronic databases and a manual search of gray literature published in the last 25 years. After data extraction and narrative synthesis of results, recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Results showed that the choice of medication depends on the severity of the child's asthma, phenotype, age, preference, and individual factors. In addition to medications, the identification of comorbidities and modifiable factors is crucial to obtaining good control. Asthma in children is heterogeneous, and its evolution varies over time. Since most recommendations for asthma management in childhood are extrapolated from clinical studies performed in adults, more clinical trials specifically designed for young children should be conducted. [ABSTRACT FROM AUTHOR]

We have developed MAGI-ACMG, a classification algorithm that allows the classification of sequencing variants (single nucleotide or small indels) according to the recommendations of the American College of Medical Genetics (ACMG) and the Association for Clinical Genomic Science (ACGS). The MAGI-ACMG classification algorithm uses information retrieved through the VarSome Application Programming Interface (API), integrates the AutoPVS1 tool in order to evaluate more precisely the attribution of the PVS1 criterion, and performs the customized assignment of specific criteria. In addition, we propose a sub-classification scheme for variants of uncertain significance (VUS) according to their proximity either towards the "likely pathogenic" or "likely benign" classes. We also conceived a pathogenicity potential criterion (P_POT) as a proxy for segregation criteria that might be added to a VUS after posterior testing, thus allowing it to upgrade its clinical significance in a diagnostic reporting setting. Finally, we have developed a user-friendly web application based on the MAGI-ACMG algorithm, available to geneticists for variant interpretation. [ABSTRACT FROM AUTHOR]

Ticagrelor is currently considered a first-line choice in dual antiplatelet therapy (DAPT) following revascularization of acute coronary syndrome (ACS). However, its use is correlated with an increased incidence of two side effects, dyspnea and bradyarrhythmias, whose molecular mechanisms have not yet been defined with certainty and, consequently, neither of the therapeutic decisions they imply. We report the case of a patient with acute myocardial infarction treated with ticagrelor and aspirin as oral antithrombotic therapy after primary percutaneous coronary intervention (PCI), manifesting in a significant bradyarrhythmic episode that required a switch of antiplatelet therapy. Starting from this case report, this article aims to gather the currently available evidence regarding the molecular mechanisms underlying these side effects and propose possible decision-making algorithms regarding their management in clinical practice. [ABSTRACT FROM AUTHOR]

Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs' extracellular matrix components to better understand molecular dysfunctions that trigger and fuel the onset and development of this disease. The bioinformatics approach we applied delineated a comprehensive overview on this fibrocellular tissue and on critical proteins that could really impact ERM physiopathology. Our interactomic analysis proposed the hyaluronic-acid-receptor cluster of differentiation 44 (CD44) as a central regulator of ERM aberrant dynamics and progression. Interestingly, the interaction between CD44 and podoplanin (PDPN) was shown to promote directional migration in epithelial cells. PDPN is a glycoprotein overexpressed in various cancers and a growing body of evidence indicates its relevant function in several fibrotic and inflammatory pathologies. The binding of PDPN to partner proteins and/or its ligand results in the modulation of signaling pathways regulating proliferation, contractility, migration, epithelial–mesenchymal transition, and extracellular matrix remodeling, all processes that are vital in ERM formation. In this context, the understanding of the PDPN role can help to modulate signaling during fibrosis, hence opening a new line of therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Insects can represent a sustainable and alternative feed ingredient to conventional feedstuffs, thanks to a rich nutritional profile, and possibly helping to reduce the feed-food competition. Among various insect species, the mulberry silkworm is of great interest. Silkworm chrysalis is a silk industry by-product, and it is a rich source of high-quality protein and healthy oil. At present, research is required to understand its potential in different food-producing animal species, optimum inclusion levels, and possible side effects. The present research contributes to provide a better understanding of the potential of silkworm chrysalis as a feedstuff for laying quails. The results of the present study demonstrated that the silkworm chrysalis meal could be used in laying quail feed formulation up to 12% inclusion, providing optimal performance and egg physical quality. The present research was conducted to determine the optimal inclusion level of full-fat silkworm chrysalis meal (SWM) into laying quails' diets, focusing on performance traits and egg physical quality. A total of 240 31-day-old female Japanese quails were randomly assigned to four dietary groups (12 replicates/treatment; 5 quails/replicate); quails were initially fed a standard commercial diet for pullets until 63 days of age. When oviposition started, the experimental groups received the following diets: a conventional corn and soybean-based diet (control diet—C) and three other diets, including 4%, 8%, or 12% of full-fat SWM (SWM4, SWM8, SWM12, respectively). Experimental diets were provided until quails reached 119 days of age. Birds displayed satisfactory productive performance throughout the trial. SWM12 and SWM8 had higher (p < 0.001) egg production but also a higher feed conversion ratio compared to C. At the end of the trial, the eggs edible portion increased, and shell weight decreased with increasing the SWM dietary inclusion level (p < 0.001). At the same time, SWM12 displayed an increase in albumen pH (p < 0.05), even though in the normal range for quail egg. Overall, full-fat SWM (up to 12%) can be considered a promising feed ingredient for laying quails, although higher inclusion levels (>8%) require special attention because SWM also contains anti-nutritional factors. [ABSTRACT FROM AUTHOR]

In this study, we fabricated adhesive patches from silkworm-regenerated silk and DNA to safeguard human skin from the sun's rays. The patches are realized by exploiting the dissolution of silk fibers (e.g., silk fibroin (SF)) and salmon sperm DNA in formic acid and CaCl2 solutions. Infrared spectroscopy is used to investigate the conformational transition of SF when combined with DNA; the results indicated that the addition of DNA provides an increase in the SF crystallinity. UV–Visible absorption and circular dichroism spectroscopy showed strong absorption in the UV region and the presence of B-form of DNA once dispersed in the SF matrix, respectively. Water absorption measurements as well as thermal dependence of water sorption and thermal analysis, suggested the stability of the fabricated patches. Biological results on cellular viability (MTT assay) of keratinocyte HaCaT cells after exposures to the solar spectrum showed that both SF and SF/DNA patches are photo-protective by increasing the cellular viability of keratinocytes after UV component exposure. Overall, these SF/DNA patches promise applications in wound dressing for practical biomedical purposes. [ABSTRACT FROM AUTHOR]

Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5–15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype–phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

This work aimed to compare targeted and untargeted approaches based on NMR data for the construction of classification models for Traditional Balsamic Vinegar of Modena (TBVM) and Balsamic Vinegar of Modena (BVM). Their complexity in terms of composition makes the authentication of these products difficult, which requires the employment of several time-consuming analytical methods. Here, 1H-NMR spectroscopy was selected as the analytical method for the analysis of TVBM and BVM due to its rapidity and efficacy in food authentication. 1H-NMR spectra of old (>12 years) and extra-old (>25 years) TVBM and BVM (>60 days) and aged (>3 years) BVM were acquired, and targeted and untargeted approaches were used for building unsupervised and supervised multivariate statistical modes. Targeted and untargeted approaches were based on quantitative results of peculiar compounds present in vinegar obtained through qNMR, and all spectral variables, respectively. Several classification models were employed, and linear discriminant analysis (LDA) demonstrated sensitivity and specificity percentages higher than 85% for both approaches. The most important discriminating variables were glucose, fructose, and 5-hydroxymethylfurfural. The untargeted approach proved to be the most promising strategy for the construction of LDA models of authentication for TVBM and BVM due to its easier applicability, rapidity, and slightly higher predictive performance. The proposed method for authenticating TBVM and BVM could be employed by Italian producers for safeguarding their valuable products. [ABSTRACT FROM AUTHOR]

Cefiderocol is a new siderophore cephalosporin that is effective against multidrug-resistant Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to evaluate the activity of this new antimicrobial agent against a collection of pathogens using broth microdilution assays and to analyze the possible mechanism of cefiderocol resistance in two resistant Klebsiella pneumoniae isolates. One hundred and ten isolates were tested, comprising 67 Enterobacterales, two Acinetobacter baumannii, one Achromobacter xylosoxidans, 33 Pseudomonas aeruginosa and seven Stenotrophomonas maltophilia. Cefiderocol showed good in vitro activity, with an MIC < 2 μg/mL, and was able to inhibit 94% of the tested isolates. We observed a resistance rate of 6%. The resistant isolates consisted of six Klebsiella pneumoniae and one Escherichia coli, leading to a resistance rate of 10.4% among the Enterobacterales. Whole-genome sequencing analysis was performed on two cefiderocol-resistant Klebsiella pneumoniae isolates to investigate the possible mutations responsible for the observed resistance. Both strains belonged to ST383 and harbored different resistant and virulence genes. The analysis of genes involved in iron uptake and transport showed the presence of different mutations located in fhuA, fepA, iutA, cirA, sitC, apbC, fepG, fepC, fetB, yicI, yicJ, and yicL. Furthermore, for the first time, to the best of our knowledge, we described two Klebsiella pneumoniae isolates that synthesize a truncated fecA protein due to the transition from G to A, leading to a premature stop codon in the amino acid position 569, and a TonB protein carrying a 4-amino acid insertion (PKPK) after Lysine 103. In conclusion, our data show that cefiderocol is an effective drug against multidrug-resistant Gram-negative bacteria. However, the higher resistance rate observed in Enterobacterales underlines the need for active surveillance to limit the spread of these pathogens and to avoid the risks associated with the emergence of resistance to new drugs. [ABSTRACT FROM AUTHOR]

Lymphoproliferative lung diseases are a heterogeneous group of disorders characterized by primary or secondary involvement of the lung. Primary pulmonary lymphomas are the most common type, representing 0.5–1% of all primary malignancies of the lung. The radiological presentation is often heterogeneous and non-specific: consolidations, masses, and nodules are the most common findings, followed by ground-glass opacities and interstitial involvement, more common in secondary lung lymphomas. These findings usually show a prevalent perilymphatic spread along bronchovascular bundles, without a prevalence in the upper or lower lung lobes. An ancillary sign, such as a "halo sign", "reverse halo sign", air bronchogram, or CT angiogram sign, may be present and can help rule out a differential diagnosis. Since a wide spectrum of pulmonary parenchymal diseases may mimic lymphoma, a correct clinical evaluation and a multidisciplinary approach are mandatory. In this sense, despite High-Resolution Computer Tomography (HRCT) representing the gold standard, a tissue sample is needed for a certain and definitive diagnosis. Cryobiopsy is a relatively new technique that permits the obtaining of a larger amount of tissue without significant artifacts, and is less invasive and more precise than surgical biopsy. [ABSTRACT FROM AUTHOR]

The host transmembrane protein SERINC5 is incorporated into retrovirus particles and inhibits HIV-1 infectivity. The lentiviral Nef protein counteracts SERINC5 by downregulating it from the cell surface and preventing its incorporation into virions. The ability of Nef to antagonize the host factor varies in magnitude between different HIV-1 isolates. After having identified a subtype H nef allele unable to promote HIV-1 infectivity in the presence of SERINC5, we investigated the molecular determinants responsible for the defective counteraction of the host factor. Chimeric molecules with a subtype C Nef highly active against SERINC5 were constructed to locate Nef residues crucial for the activity against SERINC5. An Asn at the base of the C-terminal loop of the defective nef allele was found in place of a highly conserved acidic residue (D/E 150). The conversion of Asn to Asp restored the ability of the defective Nef to downregulate SERINC5 and promote HIV-1 infectivity. The substitution was also found to be crucial for the ability of Nef to downregulate CD4, but not for Nef activities that do not rely on the internalization of receptors from the cell surface, suggesting a general implication in promoting clathrin-mediated endocytosis. Accordingly, bimolecular fluorescence complementation revealed that the conserved acidic residue contributes to the recruitment of AP2 by Nef. Altogether, our results confirm that Nef downregulates SERINC5 and CD4 by engaging a similar machinery and indicates that, in addition to the di-leucine motif, other residues in the C-terminal flexible loop are important for the ability of the protein to sustain clathrin-mediated endocytosis. [ABSTRACT FROM AUTHOR]

Europe has faced a massive spread of the varicella-zoster virus through the years. Since the introduction of an effective vaccine, complications and severe forms of chickenpox have been restricted. Nevertheless, among the population, some categories need specific care, such as pregnant women, who present one of the most fragile conditions facing this infection, both for the mother and the fetus. In this review, we highlight how the varicella-zoster virus can be dangerous during pregnancy, underlining the problem of treatment and vaccination, and collect information about the European epidemiology among this particular category of women. [ABSTRACT FROM AUTHOR]

Objectives: The surgical technique for right partial anomalous pulmonary venous return (PAPVR) depends on the location of the anomalous pulmonary veins (PVs). With this in mind, we sought to evaluate the impact of 3D heart segmentation and reconstruction on preoperative surgical planning. Methods: A retrospective study was conducted on all patients who underwent PAPVR repair at our institution between January 2018 and October 2021; three-dimensional segmentations and reconstructions of all the heart anatomies were performed. A score (the PAPVR score) was established and calculated using two anatomical parameters (the distance between the most cranial anomalous PV and the superior rim of the sinus venosus defect/the sum of the latter and the distance between the PV and the azygos vein) to predict the type of correction. Results: A total of 30 patients were included in the study. The PAPVR score was found to be a good predictor of the type of surgery performed. A value < 0.68 was significantly associated with a Warden procedure (p < 0.001) versus single/double patch repair. Conclusions: Three-dimensional heart segmentations and reconstructions improve the quality of surgical planning in the case of PAPVR and allow for the introduction of a score that may facilitate surgical decisions on the type of repair required. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing an unprecedented pandemic. Although vaccines and antivirals are limiting the spread, SARS-CoV-2 is still under selective pressure in human and animal populations, as demonstrated by the emergence of variants of concern. To better understand the driving forces leading to new subtypes of SARS-CoV-2, we infected an ex vivo cell model of the human upper respiratory tract with Alpha and Omicron BA.1 variants for one month. Although viral RNA was detected during the entire course of the infection, infectious virus production decreased over time. Sequencing analysis did not show any adaptation in the spike protein, suggesting a key role for the adaptive immune response or adaptation to other anatomical sites for the evolution of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzyme deficiencies required for cortisol biosynthesis in the adrenal cortex. The majority of CAH are due to the deficiency of the 21-hydroxylase enzyme, while 3β-hydroxysteroid dehydrogenase type 2 deficiency accounts for less than five percent of all CAH cases. We report two Moroccan twins from a spontaneous triplet pregnancy. The 46,XY newborn exhibited a disorder of sexual differentiation (DSD) with hypo virilization, while the 46,XX newborn had normal female external genitalia. In the first week of life, they showed hyponatremia and primary adrenal insufficiency with a slight 17OHP elevation and increased DHEAS and renin levels. The aCGH-SNP analysis disclosed a 8.36 Mb long contiguous stretch of homozygosity (LCSH) on chromosome 1p13.2-p11.2 including the candidate HSD3B2 gene, a LCSH of 7.3 Mb on 14q31.1-q32.11, and a 7 Mb duplication on 10q22.3-q23.2. Clinical exome sequencing revealed the biallelic c.969T > G (p.Asn323Lys) HSD3B2, likely pathogenic, variant in both of the affected twins. This case emphasizes the importance of a prompt molecular diagnosis performed through the combination of aCGH and clinical exome, both for establishment of correct therapy and for follow-up, as the newborns also carry a genomic rearrangement with possible clinical implications. [ABSTRACT FROM AUTHOR]

Acute calculus cholecystitis (ACC) is increasing in frequency within an ageing population, in which biliary tract infection, including cholecystitis and cholangitis, is the second most common cause of sepsis, with higher morbidity and mortality rates. Patient's critical conditions, such as septic shock or anaesthesiology contraindication, may be reasons to avoid laparoscopic cholecystectomy—the first-line treatment of ACC—preferring gallbladder drainage. It can aid in patient's stabilization with also the benefit of identifying the causative organism to establish a targeted antibiotic therapy, especially in patients at high risk for antimicrobial resistance such as healthcare-associated infection. Nevertheless, a recent randomized clinical trial showed that laparoscopic cholecystectomy can reduce the rate of major complications compared with percutaneous catheter drainage in critically ill patients too. On the other hand, among the possibilities to control biliary sepsis in non-operative management of ACC, according to recent meta-analysis, endoscopic gallbladder drainage showed better clinical success rate, and it is gaining popularity because of the potential advantage of allowing gallstones clearance to reduce recurrences of ACC. However, complications that may arise, although rare, can worsen an already weak clinical condition, as happened to the high surgical-risk elderly patient taken into account in our case report. [ABSTRACT FROM AUTHOR]

Background: Attachment theory represents one of the most important references for the study of the development of an individual throughout their life cycle and provides the clinician with a profound key for the purposes of understanding the suffering that underlies severe psychopathologies such as eating disorders. As such, we conducted a cross-sectional study with a mixed-methods analysis on a sample of 32 young women with anorexia nervosa (AN); this study was embedded in the utilized theoretical framework with the following aims: 1. to evaluate the state of mind (SoM) in relation to adult attachment, assuming a prevalence of the dismissing (DS) SoM and 2. to analyze the linguistic attachment profile emerging from the transcripts of the AAIs. Methods: Interviews were transcribed verbatim, coded, and analyzed using the linguistic inquiry and word count (LIWC) method. Results: The results were observed to be consistent with the referenced literature. The prevalence of a DS SoM (68.75%) is observed in the study sample, whereas the results of the lexical analysis of the stories deviate from expectations. Notably, the lexical results indicate the coexistence of the dismissing and entangled aspects at the representational level. Conclusions: The study results suggest a high level of specificity in the emotional functioning of patients with AN, with a focusing on a pervasive control of emotions that is well illustrated by the avoidant/ambivalent (A/C) strategy described in Crittenden's dynamic–maturational model. These findings and considerations have important implications for clinical work and treatment, which we believe must be structured on the basis of starting from a reappraisal of emotional content. [ABSTRACT FROM AUTHOR]

Wheezing at preschool age (i.e., before the age of six) is common, occurring in about 30% of children before the age of three. In terms of health care burden, preschool children with wheeze show double the rate of access to the emergency department and five times the rate of hospital admissions compared with school-age asthmatics. The consensus document aims to analyse the underlying mechanisms involved in the pathogenesis of preschool wheezing and define the risk factors (i.e., allergy, atopy, infection, bronchiolitis, genetics, indoor and outdoor pollution, tobacco smoke exposure, obesity, prematurity) and the protective factors (i.e., probiotics, breastfeeding, vitamin D, influenza vaccination, non-specific immunomodulators) associated with the development of the disease in the young child. A multidisciplinary panel of experts from the Emilia-Romagna Region, Italy, addressed twelve key questions regarding managing preschool wheezing. Clinical questions have been formulated by the expert panel using the PICO format (Patients, Intervention, Comparison, Outcomes). Systematic reviews have been conducted on PubMed to answer these specific questions and formulate recommendations. The GRADE approach has been used for each selected paper to assess the quality of the evidence and the degree of recommendations. Based on a panel of experts and extensive updated literature, this consensus document provides insight into the pathogenesis, risk and protective factors associated with the development and persistence of preschool wheezing. Undoubtedly, more research is needed to improve our understanding of the disease and confirm the associations between certain factors and the risk of wheezing in early life. In addition, preventive strategies must be promoted to avoid children's exposure to risk factors that may permanently affect respiratory health. [ABSTRACT FROM AUTHOR]

(1) Background: Leadless (LL) stimulation is perceived to lower surgical, vascular, and lead-related complications compared to transvenous (TV) pacemakers, yet controlled studies are lacking and real-life experience is non-conclusive. (2) Aim: To prospectively analyse survival and complication rates in leadless versus transvenous VVIR pacemakers. (3) Methods: Prospective analysis of mortality and complications in 344 consecutive VVIR TV and LL pacemaker recipients between June 2015 and May 2021. Indications for VVIR pacing were "slow" AF, atrio-ventricular block in AF or in sinus rhythm in bedridden cognitively impaired patients. LL indication was based on individualised clinical judgement. (4) Results: 72 patients received LL and 272 TV VVIR pacemakers. LL pacemaker indications included ongoing/expected chronic haemodialysis, superior venous access issues, active lifestyle with low pacing percentage expected, frailty causing high bleeding/infectious risk, previous valvular endocarditis, or device infection requiring extraction. No significant difference in the overall acute and long-term complication rate was observed between LL and TV cohorts, with greater mortality occurring in TV due to selection of older patients. (5) Conclusions: Given the low complication rate and life expectancy in this contemporary VVIR cohort, extending LL indications to all VVIR candidates is unlikely to provide clear-cut benefits. Considering the higher costs of LL technology, careful patient selection is mandatory for LL PMs to become advantageous, i.e., in the presence of vascular access issues, high bleeding/infectious risk, and long life expectancy, rendering lead-related issues and repeated surgery relevant in the long-term perspective. [ABSTRACT FROM AUTHOR]

Clinico-radiological presentation of granulomatous prostatitis (GP) is quite similar to cancer, and differential diagnosis can be very challenging. The study aims to highlight GP features based on clinical findings and multiparametric magnetic resonance imaging (mpMRI) characteristics. We retrospectively reviewed eleven patients from a cohort undergoing targeted biopsy between August 2019 and August 2021. Retrospective data including serum prostate-specific antigen (PSA) levels, PSA density and mpMRI findings were collected. Histopathology revealed seven cases of non-specific GP and four cases of specific GP as a result of intravesical Bacillus Calmette–Guérin (BCG) instillation. All lesions showed low signal intensity in T2w images, restricted diffusivity with hyperintensity in Diffusion-Weighted Imaging (DWI) and low Apparent Diffusion Coefficient (ADC) values. In Dynamic Contrast-Enhanced (DCE) imaging, the enhancement was high-peak and persistent in the majority of cases, especially in BCG-GPs. Moreover, almost all those latter lesions showed avascular core and peripheral rim enhancement. All areas identified on mpMRI were assessed with high to very high suspicion to hold prostate cancer (PIRADS v2.1 scores 4–5). Despite recent advances in imaging modalities and serological investigations, it is currently still a challenge to identify granulomatous prostatitis. Histopathology remains the gold standard in disease diagnosis. However, a differential diagnosis should be considered in patients with prior treatment with BCG. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus is the main cause of haematogenous prosthetic joint infections (PJI). We aimed to describe the prevalence and factors associated with PJI in patients with documented S. aureus bacteraemia. Methods: Adult patients with S. aureus bacteraemia and presence of prosthetic joint hospitalized in Lausanne University Hospital during a seven-year period (2015–2021) were included. Results: Among 135 patients with S. aureus bacteraemia and prosthetic joints, 38 (28%) had PJI. Multivariate analysis revealed that the presence of PJI was associated with knee arthroplasty (P 0.029; aOR 3.00, 95% CI 1.12–8.05), prior arthroplasty revision (P 0.034; aOR 3.59, 95% CI 1.10–11.74), community-acquired bacteraemia (P 0.005; aOR 4.74, 95% CI 1.61–14.01) and age < 70 years (P 0.007; aOR 9.39, 95% CI 1.84–47.85). Conclusions: PJI was common among patients with documented S. aureus bacteraemia. PJI was associated with characteristics of the prosthesis, such as prior arthroplasty revisions and knee prosthesis. [ABSTRACT FROM AUTHOR]

In the present work, the applicability of attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, coupled with chemometric tools in recognizing essential oils (EOs) for routine control, was evaluated. EOs belonging to Mentha, Cymbopogon, and Lavandula families and to S. rosmarinus and T. vulgaris species were analyzed, and the performance of several untargeted approaches, based on the synergistic combination of ATR-FTIR and Partial Least Squares Discriminant Analysis (PLS-DA), was tested to classify the species and chemotypes. Different spectra pre-processing methods were employed, and the robustness of the built models was tested by means of a Receiver Operating Characteristic (ROC) curve and random permutations test. The application of these approaches revealed fruitful results in terms of sensitivity and specificity, highlighting the potentiality of ATR-FTIR and chemometrics techniques to be used as a sensitive, cost-effective, and rapid tool to differentiate EO samples according to their species and chemotype. [ABSTRACT FROM AUTHOR]

Idiopathic epiretinal membranes (iERMs) are fibrocellular sheets of tissue that develop at the vitreoretinal interface. The iERMs consist of cells and an extracellular matrix (ECM) formed by a complex array of structural proteins and a large number of proteins that regulate cell–matrix interaction, matrix deposition and remodelling. Many components of the ECM tend to produce a layered pattern that can influence the tractional properties of the membranes. We applied a bioinformatics approach on a list of proteins previously identified with an MS-based proteomic analysis on samples of iERM to report the interactome of some key proteins. The performed pathway analysis highlights interactions occurring among ECM molecules, their cell receptors and intra- or extracellular proteins that may play a role in matrix biology in this special context. In particular, integrin β1, cathepsin B, epidermal growth factor receptor, protein-glutamine gamma-glutamyltransferase 2 and prolow-density lipoprotein receptor-related protein 1 are key hubs in the outlined protein–protein cross-talks. A section on the biomarkers that can be found in the vitreous humor of patients affected by iERM and that can modulate matrix deposition is also presented. Finally, translational medicine in iERM treatment has been summed up taking stock of the techniques that have been proposed for pharmacologic vitreolysis. [ABSTRACT FROM AUTHOR]

Preschool wheezing should be considered an umbrella term for distinctive diseases with different observable and measurable phenotypes. Despite many efforts, there is a large gap in knowledge regarding management of preschool wheezing. In order to fill this lack of knowledge, the aim of these guidelines was to define management of wheezing disorders in preschool children (aged up to 5 years). A multidisciplinary panel of experts of the Emilia-Romagna Region, Italy, addressed twelve different key questions regarding the management of preschool wheezing. Clinical questions have been formulated by the expert panel using the PICO format (Patients, Intervention, Comparison, Outcomes) and systematic reviews have been conducted on PubMed to answer these specific questions, with the aim of formulating recommendations. The GRADE approach has been used for each selected paper, to assess the quality of the evidence and the degree of recommendations. These guidelines represent, in our opinion, the most complete and up-to-date collection of recommendations on preschool wheezing to guide pediatricians in the management of their patients, standardizing approaches. Undoubtedly, more research is needed to find objective biomarkers and understand underlying mechanisms to assess phenotype and endotype and to personalize targeted treatment. [ABSTRACT FROM AUTHOR]

PRPH2 gene mutations are frequently found in inherited retinal dystrophies (IRD) and are associated with a wide spectrum of clinical phenotypes. We studied 28 subjects affected by IRD carrying pathogenic PRPH2 mutations, belonging to 11 unrelated families. Functional tests (best-corrected visual acuity measurement, chromatic test, visual field, full-field, 30 Hz flicker, and multifocal electroretinogram), morphological retino-choroidal imaging (optical coherence tomography, optical coherence tomography angiography, and fundus autofluorescence), and clinical data were collected and analyzed. Common primary complaints, with onset in their 40s, were visual acuity reduction and abnormal dark adaptation. Visual acuity ranged from light perception to 20/20 Snellen. Visual field peripheral constriction and central scotoma were found. Chromatic sense was reduced in one third of patients. Electrophysiological tests were abnormal in most of the patients. Choroidal neovascular lesions were detected in five patients. Three novel PRPH2 variants were found in four different families. Based on the present multimodal study, we identified seven distinct PRPH2 phenotypes in 11 unrelated families carrying either different mutations or the same mutation, both within the same family or among them. Fundus autofluorescence modality turned out to be the most adequate imaging method for early recognition of this dystrophy, and the optical coherence tomography angiography was highly informative to promptly detect choroidal neovascularization, even in the presence of the extensive chorioretinal atrophy phenotype. [ABSTRACT FROM AUTHOR]

Lymphedema is a chronic inflammatory disorder caused by ineffective fluid uptake by the lymphatic system, with effects mainly on the lower limbs. Lymphedema is either primary, when caused by genetic mutations, or secondary, when it follows injury, infection, or surgery. In this study, we aim to assess to what extent the current genetic tests detect genetic variants of lymphedema, and to identify the major molecular pathways that underlie this rather unknown disease. We recruited 147 individuals with a clinical diagnosis of primary lymphedema and used established genetic tests on their blood or saliva specimens. Only 11 of these were positive, while other probands were either negative (63) or inconclusive (73). The low efficacy of such tests calls for greater insight into the underlying mechanisms to increase accuracy. For this purpose, we built a molecular pathways diagram based on a literature analysis (OMIM, Kegg, PubMed, Scopus) of candidate and diagnostic genes. The PI3K/AKT and the RAS/MAPK pathways emerged as primary candidates responsible for lymphedema diagnosis, while the Rho/ROCK pathway appeared less critical. The results of this study suggest the most important pathways involved in the pathogenesis of lymphedema, and outline the most promising diagnostic and candidate genes to diagnose this disease. [ABSTRACT FROM AUTHOR]