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Many animals learn to recognize conspecifics after an early experience with them through sexual imprinting. For brood parasitic birds, it is not possible to develop conspecific recognition using cues provided by their foster parents. One solution is that a unique species-specific signal triggers the learning of additional aspects of the conspecific's phenotype. It has been proposed that for brood parasitic cowbirds, this signal is an innate vocalization, the chatter. This vocalization might act in a cross-modal learning process through which juveniles that listen to the song learn to recognize the visual characteristics of the song's producer. We trained two groups of juvenile shiny cowbirds ( Molothrus bonariensis ). In one group, individuals listened to the chatter or a heterospecific call while they observed a stuffed model of the corresponding species. In the other group, individuals listened to the call of one species (cowbird or heterospecific) while they observed the stuffed model of the other species. In the preference test, juveniles chose the model associated with the chatter, regardless of whether the model was a cowbird or a heterospecific. These results show how the auditory system through a species-specific signal can lead to cross-modal learning of visual cues allowing conspecific recognition in brood parasitic cowbirds.

Eggs are critically important for avian reproduction as all birds are oviparous. Accordingly, the recognition and care of own eggs represent the cornerstones of avian breeding, whereas the elimination of foreign objects, including brood-parasitic eggs and non-egg items from the nest are known to also increase fitness by refocusing incubation effort on the parents' own eggs. But egg recognition also plays a role in some avian obligate brood parasites' reproductive strategy through the pecking of already present eggs in the hosts' clutch to reduce nestmate competition with the parasite's own hatchling. Here we tested egg shape recognition in this parasitic egg-pecking context by exposing two different series of 3D printed models to captive obligate brood-parasitic shiny cowbirds ( Molothrus bonariensis ) in artificial nests. Natural egg-shaped models were pecked more often compared with increasingly thinner models, but there was no effect of increasing angularity on pecking rates, implying that a natural, rather than an artificial, range of variability elicited adaptive responses from parasitic cowbirds.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 10 13 vector genomes per kilogram (vg/kg), 1 × 10 14 vg/kg, and 2 × 10 14 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day −7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.

Given two non-empty graphs $H$ and $T$, write $H\succcurlyeq T$ to mean that $t(H,G)^{|E(T)|}\geq t(T,G)^{|E(H)|}$ for every graph $G$, where $t(\cdot,\cdot)$ is the homomorphism density function. We obtain various necessary and sufficient conditions for two trees $H$ and $T$ to satisfy $H\succcurlyeq T$ and determine all such pairs on at most 8 vertices. This extends results of Leontovich and Sidorenko from the 1980s and 90s. Our approach applies an information-theoretic technique of Kopparty and Rossman to reduce the problem of showing that $H\succcurlyeq T$ for two forests $H$ and $T$ to solving a particular linear program. We also characterize trees $H$ which satisfy $H\succcurlyeq S_k$ or $H\succcurlyeq P_4$, where $S_k$ is the $k$-vertex star and $P_4$ is the $4$-vertex path., Comment: 53 pages

A sequence $\pi_1,\pi_2,\dots$ of permutations is said to be "quasirandom" if the induced density of every permutation $\sigma$ in $\pi_n$ converges to $1/|\sigma|!$ as $n\to\infty$. We prove that $\pi_1,\pi_2,\dots$ is quasirandom if and only if the density of each permutation $\sigma$ in the set $$\{123,321,2143,3412,2413,3142\}$$ converges to $1/|\sigma|!$. Previously, the smallest cardinality of a set with this property, called a "quasirandom-forcing" set, was known to be between four and eight. In fact, we show that there is a single linear expression of the densities of the six permutations in this set which forces quasirandomness and show that this is best possible in the sense that there is no shorter linear expression of permutation densities with positive coefficients with this property. In the language of theoretical statistics, this expression provides a new nonparametric independence test for bivariate continuous distributions related to Spearman's $\rho$., Comment: 27 pages, 1 figure, 5 appendices included as ancillary files

The aim of this study was to describe the prevalence and epidemiology distribution of K. pneumoniae isolated at University Hospital of Campania "Luigi Vanvitelli," including the susceptibility evolution profile. Data on resistant phenotype strains, such as extended-spectrum-β-lactamase (ESBL) producers and carbapenem-resistant K. pneumoniae (CRE) isolates, were also reported. K. pneumoniae strains were collected at the Complex Operative Unit (UOC) of Virology and Microbiology from different colonization and infection sites from January 2016 to December 2020. The highest rates of isolation were in urinary samples and in respiratory and wound swabs. Antibiotics susceptibility patterns showed more than 50% of the isolates resistant to cephalosporins, fluoroquinolones and penicillin. On the other hand, from 20% to 40% of K. pneumoniae strains were resistant to carbapenems and aminoglycosides. Based on our analysis, fosfomycin, ceftazidime/avibactam and ceftolozane/tazobactam are still therapeutic alternatives. Data analysis on carbapenem class evolution in 2016-2020 showed a significant increase in resistance rates (p0.05). Increased rates in CRE and ESBL producing K. pneumoniae since 2017 were reported. Providing information on clinical characteristics and epidemiology data on contemporary K. pneumoniae evolution could help mitigate the spread of these isolates in our hospital and avert the endemic levels that have been observed in Southern Italy and in other European countries.

Paediatric obesity is a well-known risk factor for metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate the effects of laparoscopic sleeve gastrectomy (LSG) on the levels of total homocysteine (tHcy) and total glutathione (tGSH) plasma levels in children with MAFLD. Twenty-four children with severe obesity who underwent LSG were included in the study. The metabolic parameters, systemic inflammatory markers, one-carbon metabolism products, ultrasound and histological improvement were evaluated at baseline (T0M) and after 12 months from LSG (T12M). The patients exhibited a significant amelioration of several metabolic parameters at T12M. A significant reduction of steatosis was observed at ultrasound (from 72.7% of moderate-severe grade to 0% severe steatosis), accompanied by a statistically significant improvement of ballooning, portal and lobular inflammation and fibrosis. A statistically significant decrease of tumour necrosis factor circulating levels was also observed (T0M median = 290.3, IQR = 281.0–317.0 pg/mL; T12M median = 260.4, IQR = 240.0–279.0 pg/mL; p

Funder: Children’s Liver Disease Foundation; Id: http://dx.doi.org/10.13039/501100000290, Funder: European Society for Paediatric Research; Id: http://dx.doi.org/10.13039/501100008873, Funder: Virtutis Opus Foundation, Funder: European Association for the Study of the Liver; Id: http://dx.doi.org/10.13039/501100009253, Funder: For Wishdom Foundation, Funder: Italian Ministry of Health, Funder: Van den Broek Lohman Foundation, Genome-wide association studies in adults have identified variants in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6-0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective -TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down-regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the dysregulation of both 12 cancer-related circRNAs and their linRNAs in two breast cancer cell lines undergoing various treatments. We selected 14 well-known anticancer agents affecting different cellular pathways and examined their impact. Upon drug exposure circRNA/linRNA expression ratios increased, as a result of the downregulation of linRNA and upregulation of circRNA within the same gene. In this study, we highlighted the relevance of identifying the drug-regulated circ/linRNAs according to their oncogenic or anticancer role. Interestingly, VRK1 and MAN1A2 were increased by several drugs in both cell lines. However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells.

American foulbrood (AFB) is one of the most devastating infectious diseases of honey bees with a worldwide distribution. Based on clinical symptoms of AFB, the disease has been thought to have long...

Dysmetabolic conditions could drive liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), increasing susceptibility to hepatocellular carcinoma (HCC). We therefore aimed to identify novel predictive biomarkers of HCC in patients with and without liver fibrosis.A total of 1,234 patients with putative metabolic conditions and NAFLD were consecutively assessed in our outpatient clinic. Clinical and biochemical data were recorded, and then liver ultrasonography was performed annually for 5 years to detect HCC onset. For the analysis, the population was first divided according to HCC diagnosis; then a further subdivision of those who did not develop HCC was performed based on the presence or absence of liver fibrosis at time 0.Sixteen HCC cases were recorded in 5 years. None of our patients had been diagnosed with cirrhosis before HCC was detected. Compared to patients who did not develop HCC, those who did had higher liver transaminases and fibrosis scores at time 0 (This study identifies HDL-c as aVisceral adiposity and its associated conditions, such as chronic inflammation and insulin resistance, may play a pivotal role in hepatocellular carcinoma development in patients with non-alcoholic fatty liver disease. We provide new insights on the underlying mechanisms of its pathogenesis, shedding light on the involvement of low levels of "good" HDL-cholesterol. We recommend integrating dietary regimens and advice on healthy lifestyles into the clinical management of non-alcoholic fatty liver disease, with the goal of reducing the incidence of hepatocellular carcinoma.

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.

To review clinical and neuropsychological characteristics and natural history of a series of patients with temporal lobe epilepsy (TLE) and anterior temporal encephaloceles (ATE) and compare them to a similar series of TLE patients with mesial temporal sclerosis (MTS) to identify characteristics suggestive of ATE-related epilepsy.Patients with epilepsy and ATE were identified via clinic encounters and consensus epilepsy surgery conference at a Level 4 epilepsy center. The drug-resistant subset of these patients who underwent epilepsy surgery (twenty-two of thirty-five) were compared to age- and laterality-matched patients with MTS. Clinical, neuropsychological, electrophysiologic, and surgical data were abstracted through chart review.In comparison with MTS, ATE patients were more often female, had significantly later onset of epilepsy, and did not have prior febrile seizures. In addition, ATE patients were more likely to have chronic headaches and other historical features consistent with idiopathic intracranial hypertension (IIH). Failure to identify ATE on initial imaging was common. Most patients had limited temporal cortical resections sparing mesial structures. Of the twenty ATE patients who had a long-term postsurgical follow-up, seventeen (85%) had International League Against Epilepsy (ILAE) Class 1 or 2 outcomes.A shorter duration of epilepsy, female gender, and lack of history of febrile seizures may suggest ATE as an etiology of refractory TLE in adults. Targeted encephalocele resections can result in seizure freedom, underscoring the importance of encephalocele identification.

Background: The ongoing COVID-19 pandemic has challenged health systems under multiple aspects. The deep understanding of risk and prognostic factors for this disease may help not only in reducing severity and mortality but also in targeting therapies considering patients’ individual features. Liver Fibrosis is considered a complication in Non-alcoholic Fatty Liver Disease (NAFLD), being a feature of steatohepatitis (NASH), and it had already been related to an increased risk for a wide range of diseases. Methods: Here, we analysed a sample of 271 patients with moderate-to-severe SARS-CoV-2-related respiratory failure, hospitalized in a sub-intensive care Unit, with the aim of unveiling if any condition may predict their prognosis and mortality. Results: We found that non-invasive scores of liver fibrosis such as AAR, FIB-4 and mFIB-4, Forns, and AARPRI strongly predict not only in-hospital mortality but also the length of hospitalization and the eventual admission to intensive care units. Conclusions: Thus, pre-existing liver metabolic disease is a net predictor of poor prognosis in SARS-CoV-2 infected patients admitted to Sub-Intensive Care Unit.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in the pediatric population. It is a significant liver complication of obesity that also prominently affects children. Over the past decade, several noninvasive methods have been investigated for replacing liver biopsy to identify which children with NAFLD have nonalcoholic steatohepatitis (NASH) and fibrosis. These methods that aim to differentiate the type and extent of liver damage are based on two main different methodologies: a 'biological' approach centered on the quantification of circulating biomarkers; and a 'physical' approach established by analyzing different imaging data.In this review, we illustrate the state of the art and recent discoveries on noninvasive methods for the diagnosis of NAFLD, NASH, and advanced fibrosis.Currently, noninvasive tests cannot diagnose NASH or determine the degree of fibrosis. However, several lines of evidence have suggested that if these tests are used in a complementary way with other laboratory tests and imaging they have the potential to be used to monitor progression of disease and response to therapy in pediatric NAFLD. Future scientific research will focus on combining these methods with multiple potential predictors of genetic susceptibility.

Background and aims We previously demonstrated that children with Down syndrome (DS) exhibited a greater risk of steatosis than the general pediatric population. This trend was independent of obese phenotype, thus suggesting a role of genetic predisposition. Therefore, we investigated the prevalence of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) in function of genetic susceptibility and adipocytokine levels in children with DS. Methods and results A total of 84 Caucasian children with DS (age range 5–17 years), were included in this study. For all children, we collected data on anthropometric and biochemical parameters, and liver ultrasound (US). We also measured adipocytokines circulating levels and specific polymorphisms closed to NAFLD. We found a prevalence of 64.3% of liver steatosis at US, with a severe steatosis of about 4% in children with DS. The presence of steatosis in children with DS was associated with the presence of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant, which also correlated with interleukin (IL)-6 levels. Moreover, we found that the 52.4% had a waist circumference > 90th percentile, 21.4% were hypertensive, 7.14% had hyperglycemia, 9.5% had hypertriglyceridemia, and 17.9% showed high-density lipoprotein cholesterol ≤ 40 mg/dl. Finally, the IL-6 and adiponectin levels correlated with steatosis, and several adipocytokines correlated with single MetS traits in children with DS. Conclusion The present study explores for the first time potential pathomechanisms connecting pediatric NAFLD and MetS in DS. We found that the PNPLA3 variant is associated with steatosis, but not with MetS, in children with DS.

Objective Genome-wide association studies in adults have identified variants in HSD17B13 and MTARC1 as protective against NAFLD. We aimed to test their association with paediatric NAFLD, liver histology, and investigate their function using metabolomics. Design One thousand four hundred and fifty children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in PNPLA3. Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. Results rs72613567T>TA in HSD17B13 was associated with lower odds of NAFLD diagnosis (OR 0.7 (95%CI 0.6-0.9) and lower grade of portal inflammation (PA in MTARC1 was associated with lower grade of hepatic steatosis (P=0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective -TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with downregulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal-binding of MTARC1. Conclusion Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

Avian brood parasites lay their eggs into the nests of other species, which incubate them and raise the chicks until their independence. Despite living their early weeks of life surrounded by heterospecifics, young brood parasites have the ability to recognize and associate to conspecifics after independence. It has been proposed that the initial conspecific recognition develops when a young parasite encounters a unique species-specific signal that triggers the learning of other aspects of the producer of the signal. For cowbirds (Molothrus spp.), this species-specific signal is hypothesized to be the chatter call. Young birds also could express auditory biases, which in some cases lead to discrimination in favor of conspecific songs. Therefore, the perceptual selectivity for chatters might be also present in nestlings. Our aim was to assess if nestlings of the shiny cowbird (M. bonariensis) present a preferential begging response to conspecific chatter calls. We evaluated if they respond more to the parasitic vocalization than host chicks and if they respond more to the chatter than to heterospecific nonhost calls. We tested shiny cowbird chicks reared by chalk-browed mockingbirds (Mimus saturninus) or house wrens (Troglodytes aedon) and host chicks, as control species. We randomly presented to 6-day-old chicks the following playback treatments: (1) conspecific chatter calls, (2) host calls, used as positive controls, and (3) nonhost calls, used as negative control. We measured if chicks begged during the playback treatments and the begging intensity. When responding to the playback of chatter calls, shiny cowbird chicks begged at a higher frequency and more intensively than host chicks. Shiny cowbird chicks reared by mockingbirds begged more intensively to playbacks of conspecific chatter calls than to host calls, while those reared by wrens begged with a similar intensity to playbacks of conspecific chatter and host calls. On the contrary, wren nestlings begged more intensively to playbacks of the wren call than to chatter calls. Mockingbird nestlings did not beg during any treatment. None of the three species begged during the playback of nonhost calls. Our results show that the chatter call produced a preferential begging response in cowbird nestlings, which may be the beginning of a process of conspecific recognition.

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Background Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. Methods The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. Results TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. Conclusions Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

Background. Nonalcoholic fatty liver disease (NAFLD) is commonly observed in patients with type 2 diabetes (T2D). Semaglutide, a glucagon-like peptide 1 receptor agonist, may have a therapeutic role by targeting common mechanisms involved in the pathophysiology of T2D and NAFLD. The study aimed to assess the effectiveness of Semaglutide on NAFLD in patients with T2D. Methods. Forty-eight patients were treated with subcutaneous Semaglutide in add-on to metformin for 52 weeks. After the baseline visit (T0), follow-up was scheduled quarterly (T3, and T6) and then at 12 months of therapy (T12). During each visit, body composition was analyzed by phase-sensitive bio-impedance, and NAFLD was diagnosed and staged by Ultrasound (US) imaging. Surrogate biomarkers of NAFLD were also calculated and followed over time. Results. A significant decrease in anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and laboratory indices of hepatic steatosis was observed during treatment. Similarly, fat mass and visceral adipose tissue (VAT) decreased over time more than skeletal muscle and free-fat mass. US-assessed VAT thickness and the 12-point steatosis score also declined at T3 up to T12. Liver steatosis improved in most patients (70%), showing a reduction by at least one class in the semiquantitative US staging. Conclusion. Besides glucose control and body composition improvements, Semaglutide was effective in ameliorating the clinical appearance and severity of NAFLD in T2D patients.

Background and aim The association between non-alcoholic fatty liver (NAFL) and the variant rs641738 within the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene is currently uncertain, especially in the paediatric population. We examined whether there is an association between this genetic variant and NAFL in a large multicentre, hospital-based cohort of Italian overweight/obese children. Methods and results We studied 1760 overweight or obese children [mean age (SD): 11.1(2.9) years, z-body mass index (zBMI) 3.2(0.9)], who underwent ultrasonography for the diagnosis of NAFL. A subgroup of these children (n = 182) also underwent liver biopsy. Genotyping of the MBOAT7 rs641738 polymorphism was performed by TaqMan-Based RT-PCR system in each subject. Overall, 1131 (64.3%) children had ultrasound-detected NAFL; 528 (30%) had rs641738 CC genotype, 849 (48.2%) had rs641738 CT genotype, and 383 (21.8%) had rs641738 TT genotype, respectively. In the whole cohort, the interaction of MBOAT7 genotypes with zBMI was not associated with NAFL after adjustment for age, sex, serum triglycerides, serum alanine aminotransferase levels and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genotype (adjusted-odds ratio 1.02 [95% CI 0.98–1.06]). Similarly, no association was found between MBOAT7 genotypes and NAFL after stratification by obesity status. MBOAT7 genotypes were not associated with the presence of non-alcoholic steatohepatitis or the stage of liver fibrosis in a subgroup of 182 children with biopsy-proven NAFLD. Conclusions The results of this study did not show any significant contribution of MBOAT7 rs641738 polymorphism to the risk of having either NAFL on ultrasonography or NASH on histology in a large hospital-based cohort of Italian overweight/obese children.

Epstein-Barr virus (EBV) is a common herpesvirus that may cause asymptomatic infection or various diseases, such as mononucleosis, lymphoproliferative disorders and several cancers. Our objective was to estimate the prevalence of EBV among patients hospitalized in “Luigi Vanvitelli” University Hospital in the last 10 years. Our results showed that EBV seroprevalence in our geographical area was 65%. Seroprevalence increased gradually with age with no significant difference between females (49.42%) and males (50.58%). The seropositivity for primary infection was higher in patients about 5 years old, while seropositivity for past infection was predominant in patients of about 35 years old. These results underline that children in our country are still exposed to EBV. The development and the deeper use of an EBV vaccine in the early years of life could represent the solution for this infection.

Low and high leptin levels are associated with non-alcoholic fatty liver disease (NAFLD). The LncOb rs10487505 variant has been associated with body mass index (BMI), and the C allele was reported as leptin-lowering. We evaluated the association of rs10487505 with leptin levels, liver histology, and surgery-induced weight loss in youths with NAFLD.One-hundred five obese youths with NAFLD, of whom 19 undergoing laparoscopic sleeve gastrectomy (LSG), were analyzed for rs10487505 and leptin circulating levels.The G allele frequency was lower in youths with NAFLD than in controls (p = 0.049). No difference was found in anthropometrics, biochemistry and histology between G allele carriers and CC homozygotes, except for leptin levels (p = 0.016). Leptin correlated with body weight, BMI, BMI-z score, waist circumference, insulin resistance/sensitivity, and triglycerides (p ≤ 0.01). A multivariable regression model including body weight and homeostasis model assessment of insulin resistance was a good predictor of plasma leptin (RLncOb rs10487505 variant was associated with pediatric NAFLD and high leptin levels, and with weight and leptin reduction after LSG in youths.The interplay of environment, genetics and epigenetics is crucial inflating the risk of non-alcoholic fatty liver disease (NAFLD). Several long non-coding RNA (LncRNAs) are found associated with NAFLD pathogenesis. Here, we evaluated the impact of the genetic variant rs10487505 in LncOb which is involved in the regulation of leptin gene expression. The LncOb rs10487505 is associated with increased levels of leptin, but not with liver histology, in youths with NAFLD. The LncOb rs10487505 was also associated with the significant decrease of leptin and body weight after bariatric surgery.

Vascular injuries that occur during traffic accidents are a commonly neglected aspect that can add more detail to the framework of a case. In this study, we analysed a case series of 150 traffic accidents, 39 of which were marked by microscopically identifiable vascular lesions. The purpose was to identify the presence of carotid injuries in individuals who died due to traffic accidents and had nonpenetrating trauma of the neck. We focused on the discrepancies regarding the macroscopical aspect and the histology and demonstrated how histological analysis of the carotids in cases of trauma can reveal injuries that are attributable to the trauma itself. We conducted a histological analysis of the lesions to describe their distribution and type and investigate potential correlations. The study offers insight on how to examine road accidents that involve traumatic injury of the carotid arteries. Indeed the main task of the forensic pathologist in the case of death is to establish the existence of a causal relationship between the micro- or macroscopic alterations observed in the autopsy and the traumatic event that led to the death of the subject. Thus, further morphological elements were provided to the forensic practitioners that may reveal injuries attributable to the trauma itself and should be evaluated in cases of trauma in traffic accidents.

Background and objectives Lung Ultrasound Score (LUS) identifies and monitors pneumonia by assigning increasing scores. However, it does not include parameters, such as inferior vena cava (IVC) diameter and index of collapse, diaphragmatic excursions and search for pleural and pericardial effusions. Therefore, we propose a new improved scoring system, termed “integrated” lung ultrasound score (i-LUS) which incorporates previously mentioned parameters that can help in prediction of disease severity and survival, choice of oxygenation mode/ventilation and assignment to subsequent areas of care in patients with COVID-19 pneumonia. Methods Upon admission at the sub-intensive section of the emergency medical department (SEMD), 143 consecutively examined COVID-19 patients underwent i-LUS together with all other routine analysis. A database for anamnestic information, laboratory data, gas analysis and i-LUS parameters was created and analyzed. Results Of 143 enrolled patients, 59.4% were male (mean age 71 years) and 40.6% female. (mean age 79 years: p = 0.005). Patients that survived at 1 month had i-LUS score of 16, which was lower than that of non-survivors (median 20; p = 0.005). Survivors had a higher PaO2/FiO2 (median 321.5) compared to non-survivors (median 229, p p p = 0.005). In non-survivors, the serum values of different significant COVID indicators were severely expressed. The i-LUS score was higher (median 20) in patients who required non-invasive ventilation (NIV) than in those treated only by oxygen therapy (median 15.42; p = 0.003). The odds ratio for death outcome was 1.08 (confidence interval 1.02–1.15) for each point increased. At 1-month follow-up, 65 patients (45.5%) died and 78 (54.5%) survived. Patients admitted to the high critical ward had higher i-LUS score than those admitted to the low critical one (p Conclusions i-LUS could be used as a helpful clinical tool for early decision-making in patients with COVID-19 pneumonia.

SummaryThe detection/quantification in honey of spores of the bacterial pathogen Paenibacillus larvae, the etiological agent of the American Foulbrood (AFB) infectious disease of honey bee, represents a useful diagnostic tool to identify apiaries at risk of infection and carry out focused prevention measures. Plate count is currently the recommended method used to analyze presence and number of spores for this pathogen. However, its validity needs to be re-assessed since P. larvae field strains have a low rate of germination in culture media.Therefore, in this study, culture-dependent P. larvae detection/quantification was compared with quantitative PCR (qPCR) based analysis for 139 honey samples collected in 2017 and 2018 from as many apiaries in the Abruzzo region. According to qPCR based detection, 58.27% samples were positive for P. larvae, while only 33.8 % samples were positive by plate count.Moreover, the levels of contamination with the two methods differed for most samples. Potential false positives were obtained by plate count for 12.9% samples that were negative with the qPCR test. On the other hand, 26.6% samples were culture negative but qPCR positive, suggesting that not all the field strains were able to develop in plate. This was confirmed by obtaining P. larvae growth from those samples after supplementing the medium with germination stimulants.Results strongly suggested the necessity to improve culture methods or replace them with molecular detection/quantification for a more reliable AFB risk estimation.

Muscular dystrophy (MD) is a group of progressive genetic diseases affecting the musculature that are characterized by inflammatory infiltrates, necrosis and connective tissue and fat replacement of the affected muscles. Unfortunately, treatments do not exist for the vast majority of MD patients. Adeno-associated viral vector (AAV)-based gene therapy is thus emerging as a potential treatment for many types of MD. Treatments strategies based on AAV are being adapted for replacement of mutant disease-causing genes, knockdown of dominant disease-causing genes using antisense oligonucleotides or inhibitory RNAs, delivery of gene editing tools such as clustered regularly interspaced short palindromic repeats/Cas9 and effecting alterations in pre-mRNA splicing and by manipulating expression levels of modifier genes. Translational and clinical trial work focused on these types of AAV treatments for Duchenne MD, various limb girdle MDs, myotonic dystrophy 1, facioscapulohumeral MD, dysferlinopathies and congenital MDs are discussed here, with a focus on recent studies, pre-clinical large animal work and many promising ongoing and upcoming AAV clinical trials.

Non-alcoholic fatty liver disease (NAFLD)-related liver fibrosis results in the encapsulation of injured liver parenchyma by a collagenous scar mainly imputable to hepatic stellate cells’ activation. Approved pharmacological treatments against NAFLD-related fibrosis are still lacking, but natural compounds such as hydroxytyrosol (HXT) and vitamin E (VitE), are emerging as promising therapeutic opportunities. In this study, the potential anti-fibrotic effect of HXT + VitE combination therapy was investigated in vitro and in vivo. In particular, tumor growth factor (TGF)-β-activated LX-2 cells as an in vitro model, and carbon tetrachloride plus a Western diet as a mice model were employed. The effect of HXT + VitE on fibrosis was also investigated in children with biopsy-proven NAFLD. Our results demonstrated that HXT + VitE caused a reduction of proliferation, migration, contractility, and expression of pro-fibrogenic genes in TGF-β-activated LX-2 cells. HXT + VitE treatment also antagonized TGF-β-dependent upregulation of pro-oxidant NOX2 by interfering with nuclear translocation/activation of SMAD2/3 transcription factors. The mouse model of NAFLD-related fibrosis treated with HXT + VitE showed a marked reduction of fibrosis pattern by histology and gene expression. Accordingly, in children with NAFLD, HXT + VitE treatment caused a decrease of circulating levels of PIIINP and NOX2 that was supported over time. Our study suggests that HXT + VitE supplementation may improve NAFLD-related fibrosis.

Bile acid (BA) species and the gut microbiota (GM) contribute to intestinal mucosa homeostasis. BAs shape the GM and, conversely, intestinal bacteria with bile salt hydrolase (BSH) activity modulate the BA pool composition. The mutual interaction between BAs and intestinal microorganisms also influences mucosal barrier integrity, which is important for inflammatory bowel disease (IBD) pathogenesis, prevention and therapy. High levels of secondary BAs are detrimental for the intestinal barrier and increase the intestinal inflammatory response and dysbiosis. Additionally, a lack of BSH-active bacteria plays a role in intestinal inflammation and BA dysmetabolism. Thus, BSH-competent bacteria in probiotic formulations are being actively studied in IBD. At the same time, studies exploring the modulation of the master regulator of BA homeostasis, the Farnesoid X Receptor (FXR), in intestinal inflammation and how this impacts the GM are gaining significant momentum. Overall, the choice of probiotic supplementation should be a peculiar issue of personalized medicine, considering not only the disease but also the specific BA and metabolic signatures of a given patient.

Even if the Amussat's sign is known since the mid-19th century, few studies have been made in order to assess its real occurrence. In particular, the histopathologic examination of the Amussat's sign lacks in the medicolegal literature. The review of the literature shows indeed a significant range of variability (from 1.1 % up to 25 %) regarding the macroscopic detection of the Amussat's sign. In this study, the authors report that the identification of a vital Amussat's sign is important and may require the immunohistochemical staining for the Glycophorin A (a marker of vital reaction). The victim was a 63-year-old man, who was found suspended from the staircase with a rope. Both the carotid arteries were opened in situ by using fine scissors with blunt tips. A horizontal lesion (length 4 mm) of the intima of the left common carotid artery was documented. A sample was obtained; then, a standard post-fixative histopathologic examination and immunohistochemical staining for the Glycophorin A were carried out. The standard histopathologic examination only revealed the intimal laceration with a poor hemorrhagic infiltration. However, the immunohistochemical staining for the Glycophorin A allowed the clear identification of the hemorrhagic infiltration, which was documented both in the intimal laceration and in the periadventitial soft tissues. The immunohistochemical staining for the Glycophorin A can identify the vitality of an Amussat's sign. When an Amussat's sign is documented, the Glycophorin A may therefore help the forensic pathologist to differentiate a hanging death from a postmortem suspension of the body.

Objective Depression and anxiety disorders are common among patients with epilepsy (PWE). These comorbidities have been shown to influence prognosis and may have a greater impact on quality of life than seizure control. Despite guideline recommendations and expert consensus to regularly screen for and treat both conditions, there is evidence that they are underdiagnosed and undertreated. Our goal was to test a novel screening method to determine if it would increase the rate of detecting and treating depression and anxiety disorders among PWE. Method The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and the Brief Epilepsy Anxiety Survey Instrument (brEASI) were selected as validated screening instruments for depression and anxiety disorders, respectively. They were sent via an electronic medical record-linked patient portal to all patients of four epileptologists 48 h prior to their clinic appointment. We evaluated whether this increased the rate of detecting and treating depression and anxiety disorders relative to a historical control group. Results A total of 563 patients were included of whom 351 were sent the screening instruments. 62.7% of patients completed the screening instruments of whom 47.7% screened positive for either depression only (16.4%), anxiety disorders only (5.5%) or both (25.9%); a statistically significant increase relative to the control group. There was also a significantly increased proportion of patients for whom treatment was initiated for depression (p Conclusions We identified an easily applicable and efficient means of enhancing detection and treatment rates for depression and anxiety disorders among PWE in a busy clinic setting.

OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in both adults and children. Along with obesity and metabolic syndrome, genetic predisposition influences the progression of NAFLD. Here, we investigated the effect of lifespan/healthspan-related single nucleotide polymorphisms (SNPs) on metabolically associated fatty liver disease in children. METHODS We evaluated the impact of 10 SNPs involved in both human liver/metabolic diseases and healthspan (interleukin-6 [IL-6] rs1800795, antisense non coding RNA in the INK4 locus (ANRIL) rs1556516, SH2B3/ATXN2 rs7137828, FURIN rs17514846, TP53 rs1042522, APOC3 rs2542052, KL rs9536314, KL rs9527025, SIRT6 rs107251, FOXO3 rs2802292) on NAFLD-related metabolic and liver features in 177 pediatric patients with biopsy-proven NAFLD, by comparing them to 146 healthy controls. We then applied a multidimensional reduction (MDR) case-control analysis of SNP-SNP interactions, to identify the joint effect of analyzed SNPs in predicting NAFLD and associated features. RESULTS Discrete SNPs were significantly associated with individual metabolic NAFLD features, but none of them significantly associated with NAFLD diagnosis. By testing potential synergies using the MDR approach, the best combination to diagnose NAFLD (P = 0.0011) resulted in the one encompassing IL-6 rs1800795 and ANRIL rs1556516. Consistently, the risk combinations suggested by SNP-SNP analysis strongly associated with a higher level of fasting plasma blood glucose level (P = 0.024). CONCLUSION In conclusion, here we demonstrated a synergic interaction between IL-6 rs1800795 and ANRIL rs1556516 in the diagnosis of NAFLD, and NAFLD-associated hyperglycemia in children. Larger studies are required to confirm our findings and to elucidate mechanisms by which the genetic interaction between these two genes influences healthspan in pediatric NAFLD.

The SARS-CoV-2 pandemic has caused approximately 6.3 million deaths, mainly due to the acute respiratory distress syndrome or multi-organ failure that characterizes COVID-19 acute disease. Post-acute COVID-19 syndrome, also known as long-COVID, is a condition characterized by a complex of symptoms that affects 10–20% of the individuals who have recovered from the infection. Scientific and clinical evidence demonstrates that long-COVID can develop in both adults and children. It has been hypothesized that multi-organ effects of long-COVID could be associated with the persistence of virus RNA/proteins in host cells, but the real mechanism remains to be elucidated. Therefore, we sought to determine the effects of the exogenous expression of the papain-like protease (PLpro) domain of the non-structural protein (NSP3) of SARS-CoV-2 in polarized human airway (Calu-3), intestinal (Caco-2), and liver (HepG2) epithelial cells, and to evaluate the ability of the natural antioxidant hydroxytyrosol (HXT) in neutralizing these effects. Our results demonstrated that PLpro was able to induce a cascade of inflammatory genes and proteins (mainly associated with the interferon pathway) and increase the apoptotic rate and expression of several oxidative stress markers in all evaluated epithelial cells. Noteably, the treatment with 10 μM HXT reverted PL-pro-dependent effects almost completely. This study provides the first evidence that SARS-CoV-2 PLpro remaining in host cells after viral clearance may contribute to the pathogenetic mechanisms of long-COVID. These effects may be counteracted by natural antioxidants. Further clinical and experimental studies are necessary to confirm this hypothesis.

Literature on electrocution in Italy is limited. The authors have focused their attention on the use of scanning electron microscope/energy-dispersive X-ray analysis in order to evaluate the current mark even on paraffin-embedded samples. A total of 24,104 autopsies were performed at the Section of Legal Medicine of Milan (1993–2017); all cases of death caused by electrocution (low and high voltage) were selected. We assessed a regular histological examination, a toxicological examination and detected metallisation with energy-dispersive X-ray spectroscopy analysis on paraffin-embedded tissues of typical current marks. We collected 27 high-voltage fatalities and five cases of low-voltage suicide electrocution; the technique revealed itself as sensitive. In all cases, microscopic examination highlighted the typical signs of electric current and thermal damage but the histochemical specific stainings for copper and iron gave negative results. Scanning electron microscope/energy-dispersive X-ray analysis, assessed on these same samples, even when paraffin-embedded, however, enabled us to detect these elements and differentiate between the various metal residues involved in the electrocution process. Based on their experience, authors advise the use of scanning electron microscope/energy-dispersive X-ray analysis on electrocution deaths to provide information for forensic diagnosis.

BACKGROUND Nonalcoholic fatty liver disease (NAFLD), a chronic liver disease in children, ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). We investigated the role of Angiopoietin-2 (Ang-2) as a biomarker for pediatric NAFLD-related liver damage. METHODS We assessed the plasma levels of Ang-2 and cytokeratin-18 (CK18) fragments and their association with histologic activity in 76 children with NAFLD and 28 controls. RESULTS The mean plasma levels of Ang-2 and CK18 were higher in children with NAFLD than in age-matched controls (Ang-2 155.4 ± 72.5 vs 7.5 ± 2.3 ng/mL, p

Additional file 7: Figure S2. Evaluation of the IC50 values of TAE226 and SOR on HCC cell viability after 2 and 5 days. Cell viability, measured by XTT assay, after 2 and 5 days from treatment with TAE226 or SOR, in HepG2 and Huh7 cells. Values are the mean OD �� SD of three independent experiments repeated at least in duplicate. Data were analysed by ANOVA. ***p

Additional file 6: Figure S1. FAK phosphorylation in HCC cells after IC50 values of treatments. Quantitative analysis of pTyr397FAK expression after 48 h of treatment with the different drugs, in HepG2 and Huh7 cells. Values are the mean arbitrary units �� SD of at least three independent experiments. Data were analysed by 2-tailed Student���s t test. *p

Additional file 10: Figure S5. Analysis of FAK nuclear interaction with specific epigenetics regulators. (A) Coomassie-stained 1D SDS-PAGE gels used for the in-gel digestions of nuclear immunoprecipitates of FAK in HCC cells. The photographs showed gel lanes excision into 10 bands for mass spectrometry characterization of FAK nuclear interactors. (B) Pipeline employed for the analysis of proteomics data.

Additional file 2: Table S2. In vivo antitumor efficacy of TAE226>SOR combination on orthotopic liver tumour.

Additional file 9: Figure S4. Pilot study for quantitative setting of TAE226 concentration in a heterotopic HepG2 xenograft model of HCC. (A) Quantitative analysis of tumour weight at various time points in NT animals or after TAE226 treatments. P values were calculated at day 12 using an unpaired two-tailed t-test, between treated and untreated tumours. **** p

Additional file 1: Table S1. List of antibodies.