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Notwithstanding several research efforts in the past years, robust and replicable molecular signatures for autism spectrum disorders from peripheral blood remain elusive. The available literature on blood transcriptome in ASD suggests that through accurate experimental design it is possible to extract important information on the disease pathophysiology at the peripheral level. Here we exploit the availability of a resource for molecular biomarkers in ASD, the Italian Autism Network (ITAN) collection, for the investigation of transcriptomic signatures in ASD based on a discordant sibling pair design. Whole blood samples from 75 discordant sibling pairs selected from the ITAN network where submitted to RNASeq analysis and data analyzed by complementary approaches. Overall, differences in gene expression between affected and unaffected siblings were small. In order to assess the contribution of differences in the relative proportion of blood cells between discordant siblings, we have applied two different cell deconvolution algorithms, showing that the observed molecular signatures mainly reflect changes in peripheral blood immune cell composition, in particular NK cells. The results obtained by the cell deconvolution approach are supported by the analysis performed by WGCNA. Our report describes the largest differential gene expression profiling in peripheral blood of ASD subjects and controls conducted by RNASeq. The observed signatures are consistent with the hypothesis of immune alterations in autism and an increased risk of developing autism in subjects exposed to prenatal infections or stress. Our study also points to a potential role of NMUR1, HMGB3, and PTPRN2 in ASD.

During autophagy, the coordinated actions of autophagosomes and lysosomes result in the controlled removal of damaged intracellular organelles and superfluous substrates. The evolutionary conservation of this process and its requirement for maintaining cellular homeostasis emphasizes the need to better dissect the pathways governing its molecular regulation. In our previously performed high-content screen, we assessed the effect of 1530 RNA-binding proteins on autophagy. Among the top regulators, we identified the eukaryotic translation initiation factor 4A-3 (eIF4A3). Here we show that depletion of eIF4A3 leads to a potent increase in autophagosome and lysosome biogenesis and an enhanced autophagic flux. This is mediated by the key autophagy transcription factor, TFEB, which becomes dephosphorylated and translocates from the cytoplasm to the nucleus where it elicits an integrated transcriptional response. We further identified an exon-skipping event in the transcript encoding for the direct TFEB kinase, GSK3B, which leads to a reduction in GSK3B expression and activity. Through analysis of TCGA data, we found a significant upregulation of eIF4A3 expression across several cancer types and confirmed the potential relevance of this newly identified signaling axis in human tumors. Hence, our data suggest a previously unrecognized role for eIF4A3 as a gatekeeper of autophagy through the control of TFEB activation, revealing a new mechanism for autophagy regulation.

Background Strongyloidiasis caused by Strongyloides stercoralis is a soil-transmitted helminthiasis affecting an estimated 370 million people and considered one of the most neglected tropical diseases. Although mostly distributed in tropical and subtropical areas, autochthonous infections have also been documented in north-eastern Italy, even though the transmission presumably stopped decades ago. Because of its peculiar auto-infective cycle, strongyloidiasis can persist lifelong, but the pathophysiological mechanisms associated with the maintenance of such a chronic infection are yet to be fully deciphered. Methods Serum levels of 23 immune factors were retrospectively assessed in a subgroup of participants in a randomised clinical trial for the treatment of strongyloidiasis (Strong Treat). Here we included Italian subjects born between 1931 and 1964 and diagnosed with strongyloidiasis between 2013 and 2017 (Ss+, n = 32). Serum samples obtained before (BT) and 6 months (6M AT) after ivermectin treatment, as well as from age- and gender-matched uninfected controls (CTRL, n = 34) were analysed. Results The assessed immune factors showed a general reduced concertation in Ss+ patients and a lack of association with eosinophilia. In our cohort, we did not observe the classical shift towards a type 2 immune response, since Th1 and Th2 cytokines were mostly unaltered. Instead, we observed chemokines as particularly affected by the presence of the parasite, since IL-8, CCL3, CCL4 and CCL5 were significantly reduced in concentration in Ss+ subjects compared to CTRL, suggesting that immune cell recruitment to the infection site might be dampened in these patients. This observation was further sustained by a significant increase of CCL4, CCL5 and CCL11 concentrations 6M AT. A significant raised systemic concentration of three growth factors, bFGF, PDGF-BB and IL-7 (haematopoietic growth factor) was also observed post-treatment, indicating a potential involvement in restoring tissue integrity and homeostasis following parasite elimination. Conclusions These preliminary data suggest that, in order to survive for such a long period, S. stercoralis might suppress host responses that could otherwise result in its ejection. Our results offer novel insights in the potential mechanisms of disease tolerance that might take place during this chronic infection, including a potential T-cell hypo-responsiveness and a role for chemokines.

Study design Prospective observational study. Objective To evaluate pelvic MRI muscle signal changes and their association with early heterotopic ossification (HO) in patients with spinal cord injuries. Setting National Spinal Injuries Unit, Stoke Mandeville, UK. Methods Forty patients were imaged with at least two interval magnetic resonance (MR) studies of the pelvis in the first 6 months following a spinal cord injury. Scans were reviewed and scored for heterotopic ossification, muscle signal change and extent of muscle involvement. Results Muscle signal change was present in 28 (70%) on the initial MRI and 31 (77%) by the second study. Six patients developed MR changes of prodromal or immature heterotopic ossification (15%). No restricted diffusion was demonstrated and no patient developed mature HO. Patients developing MR changes of early HO were more likely to have grade 3 muscle changes. Conclusion Increased T2 muscle signal is common following cord injury, is frequently progressive in the subacute period and is associated with complete injury and early MR signs of heterotopic ossification.

Highlights • We conducted a retrospective study on 61 patients admitted to the ICU • We investigated the relationship among SARS-CoV-2 and bacterial/fungal colonization • Among positive bronchial aspirates, 80 % were colonized by fungi or P. aeruginosa • No multidrug-resistant bacteria or fungi were isolated • The failure in the regulation of defenses against pathogens other than SARS-CoV-2

Metabolic constrains induce transcriptional deregulation of CD8+ T cells in pancreatic tumor microenvironment, driving progressive dysfunction. Here, metabolic reprogramming through enforced very-long-chain acyl-CoA dehydrogenase expression enhances intratumor T cells survival and persistence, overcoming a major hurdle to immunotherapy for PDA., CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.

Bacterial vaginosis (BV) is one of the most frequent causes of vaginal discharge in women during reproductive age worldwide. This disease is characterized by the replacement of the normal vaginal flora with an overgrowth of anaerobic bacteria most of them producing sialidase enzyme. BV is associated with an increased risk of adverse outcomes in pregnancy and susceptibility to several sexually transmitted diseases. In the present study, we evaluated the detection of sialidase activity by OSOM BVBlue test in association with routine microbial cultures and Nugent’s score, considered as the gold standard, for the diagnosis of bacterial vaginosis. Three vaginal swabs were collected from 352 women older than 12 years in age. A swab collected into Amies transport medium was employed for standard microbial cultures, a FLOQSwab for Gram stain, and a second FLOQSwab for the BVBlue test. According to Nugent’s score, BV frequency was 16.5 % (58 samples). The sensitivity of microbial culture and BVBlue test, when compared with Nugent’s score, was 69.8 % and 39.6 %, respectively. However, BVBlue test detected five cases with no bacterial growth in culture, whereas 14 samples with bacterial cultures positive for Gardnerella vaginalis showed a BVBlue test negative. The combination of microbial culture and BVBlue test increased the sensitivity to 75 % compared with Nugent’s score. In conclusion, BVBlue test alone appears not to be an efficient screening test, but, when associated with microbial cultures, can improve the diagnosis of BV

We profiled antibody responses in a cohort of recipients of the BTN162b2 mRNA vaccine who were either immunologically naïve (n=50) or had been previously infected with SARS-CoV-2 (n=51). Of the previously infected, 25 and 26 were infected during the first and second pandemic waves in Italy, respectively; the majority of those from the first wave had corresponding waning immunity with low to undetectable levels of anti-S antibodies and low anti-N antibodies. We observed in recipients who had been previously infected that spike-specific IgG and pseudovirus neutralization titers were rapidly recalled by a single vaccine dose to higher levels than those in naïve recipients after the second vaccine dose, irrespective of waning immunity. In all recipients, a single vaccine dose was sufficient to induce a potent IgA response that was not associated with serum neutralization titers.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, which has been found associated with dysfunctional mitochondria. In order to advance our understanding of the complex molecular mechanisms underlying this disease, we analyzed mitophagy, a process fundamental for the elimination of damaged mitochondria through the autophagic process, in peripheral blood mononuclear cells (PBMCs) of MS patients. Through a genetic analysis carried out on 203 MS patients and 1000 healthy controls, we identified a natural variant of CALCOCO2/NDP52, a well-known autophagic receptor, associated with and protective in MS. Structural modeling of the CALCOCO2 variant and functional studies highlighted an amino acid substitution (G140E) located near the LC3-interacting region (LIR) motif of CALCOCO2, crucial in controlling mitophagy. In addition, we found that among PBMCs, CALCOCO2 is mainly expressed in B cells and, by mediating mitophagy, it reduces pro-inflammatory cytokine production following stimulation of these cells. Here we summarize these recent findings, discuss the putative protective roles of CALCOCO2 in B cells and its novel association with an autoimmune disease such as MS.

Background: IgG antibodies specific for the SARS-CoV-2 Spike protein are under intensive investigation for the urgent need to identify a correlate of protective immunity in individuals vaccinated with licensed and candidate COVID-19 vaccines. Limited data are available on vaccine-elicited IgM antibodies and their potential implication in immunity to SARS-CoV-2. Methods: We performed a longitudinal study to quantify IgG and IgM antibodies specific for the SARS-CoV-2 spike protein (IgG-S and IgM-S) in 1873 health care worker (HCW) recipients of the BNT162b2 (Comirnaty) vaccine. Samples were collected before administration (T0), at the second dose (T1) and three weeks after the second dose (T2). The cohort included 1584 immunologically naive to SARS-CoV-2 (IN) and 289 had a history of previous infection (PI). Findings: In IN we identified three patterns of responses: (a) IgG positive/IgM negative (36.1%), (b) coordinated IgM-S/IgG-S responses appearing three weeks after the first dose (37.4%) and (c) delayed IgM appearing after IgG (26.3%). Coordinated IgM-S/IgG-S responses were associated with higher IgG titers. Of the 289 PI vaccinees, 64.5% were IgM-S positive before vaccination, whereas 32% and 3.5% developed IgM-S after the first and second vaccine dose respectively. IgM-S positive sera had higher pseudovirus neutralization titers compared to the IgM-S negative. Similar results were observed in individuals who received either Moderna or Astrazeneca. Interpretation: Coordinated expression of IgG-S and IgM-S after vaccination was associated with a significantly more efficient response in both antibody titers and virus-neutralizing activity, representing a potential correlate of protection. Instead, the unconventional IgG-S positive/IgM-S negative responses may be suggestive of a recruitment of cross coronaviruses immunity by vaccination, warranting further investigation. Funding Information: This work was supported by the Italian Ministry of Health under “Fondi Ricerca Corrente”- L1P5 and “Progetto Ricerca Finalizzata COVID-2020-12371675” to IRCCS Sacro Cuore Don Calabria Hospital, by FUR 2020 Department of Excellence 2018-2022, MIUR, Italy and by The Brain Research Foundation Verona.

Current literature regarding systemic autoimmune diseases in X-chromosome aneuploidies is scarce and limited to case reports. Our aim was to evaluate the frequency of anti-nuclear (ANAs), extractable nuclear (ENA), anti-double-stranded DNA (dsDNAs), anti-smooth muscle (ASMAs) and anti-mitochondrial (AMAs) antibodies in a large cohort of adults with Klinefelter's syndrome (KS, 47,XXY) and rare higher-grade sex chromosome aneuploidies (HGAs) for the first time. Sera from 138 X-chromosome aneuploid patients [124 adult patients with 47,XXY KS and 14 patients with HGA (six children, eight adults)] and 50 age-matched 46,XY controls were recruited from the Sapienza University of Rome (2007–17) and tested for ANAs, ENAs, anti-dsDNAs, ASMAs and AMAs. Non-organ-specific immunoreactivity was found to be significantly higher in patients with 47,XXY KS (14%) than in the controls (2%, p = 0.002). Among all the antibodies investigated, only ANAs were observed significantly more frequently in patients with 47,XXY KS (12.1%) than in the controls (2%, p = 0.004). No anti-dsDNA immunoreactivity was found. Stratifying by testosterone replacement therapy (TRT), non-organ-specific autoantibody frequencies were higher in TRT-naive (p = 0.01) and TRT-treated groups than in controls. No patients with HGA were found positive for the various autoantibodies. Non-organ-specific autoantibodies were significantly present in 47,XXY adult patients. Conversely, HGAs did not appear to be target of non-organ-specific immunoreactivity, suggesting that KS and HGAs should be considered as two distinct conditions. The classification and diagnosis of systemic autoimmune diseases is frequently difficult. To support a correct clinical evaluation of KS disease and to prevent eventual secondary irreversible immune-mediated damages, we highlight the importance of screening for non-organ-specific autoimmunity in Klinefelter's syndrome.

The antibody response to SARS-CoV-2 mRNA vaccines in individuals with waning immunity generated by a previous SARS-CoV-2 infection, as well as the patterns of IgA and IgM responses in previously infected and in naive individuals are still poorly understood. We performed a serology study in a cohort of BTN162b2 mRNA vaccine recipients who were immunologically naive (N, n = 50) or had been previously infected with SARS-CoV-2 (P.I., n = 51) during the first (n = 25) or second (n = 26) pandemic waves in Italy, respectively. We measured IgG, IgM and IgA antibodies against the SARS-CoV-2 Spike (S) and IgG against the nucleocapsid (N) proteins, as well as the neutralizing activity of sera collected before vaccination, after the first and second dose of vaccine. Most P.I. individuals from the first pandemic wave who showed declining antibody titres responded to the first vaccine dose with IgG-S and pseudovirus neutralization titres that were significantly higher than those observed in N individuals after the second vaccine dose. In all recipients, a single dose of vaccine was sufficient to induce a potent IgA response that was not associated with serum neutralization titres. We observed an unconventional pattern of IgM responses that were elicited in only half of immunologically naive subjects even after the second vaccine dose. The response to a single dose of vaccine in P.I. individuals is more potent than that observed in N individuals after two doses. Vaccine-induced IgA are not associated with serum neutralization. Dalle Carbonare et al. perform a serology study in participants with a prior infection of SARS-CoV-2 and those who are SARS-CoV-2-naive, who received two doses of the Pfizer-BioNTech BNT162b2 vaccine. After a single dose they observe a quicker recall of pseudovirus neutralization titres in previously-infected participants and a potent IgA response in both groups that was not associated with serum neutralization titres. Antibodies are proteins produced by the immune system that are released into the bloodstream and help fight infections. To understand how the immune system responds to COVID-19 vaccination in individuals who have had a previous SARS-CoV-2 infection, we compared the types and levels of antibodies produced after first and second doses of the vaccine with those of individuals who had never been infected. We found that one dose of vaccine, even several months after the infection, was sufficient to boost a very efficient response by eliciting specific types of antibodies, some of which were and some that were not able to neutralize the virus. We also observed an unusual antibody profile in almost half of individuals who had not been infected. These findings may help better understand the immune response to COVID-19 vaccines.

On March 11, 2020, Italy imposed a national lockdown to curtail the spread of severe acute respiratory syndrome coronavirus 2. We estimate that, 14 days after lockdown, the net reproduction number had dropped below 1 and remained stable at »0.76 (95% CI 0.67-0.85) in all regions for >3 of the following weeks.

Following the SARS-CoV-2 pandemic, several clinical trials have been approved for the investigation of the possible use of mAbs, supporting the potential of this technology as a therapeutic approach for infectious diseases. The first monoclonal antibody (mAb), Muromonab CD3, was introduced for the prevention of kidney transplant rejection more than 30 years ago; since then more than 100 mAbs have been approved for therapeutic purposes. Nonetheless, only four mAbs are currently employed for infectious diseases: Palivizumab, for the prevention of respiratory syncytial virus (RSV) infections, Raxibacumab and Obiltoxaximab, for the prophylaxis and treatment against anthrax toxin and Bezlotoxumab, for the prevention ofClostridium difficilerecurrence. Protozoan infections are often neglected diseases for which effective and safe chemotherapies are generally missing. In this context, drug resistance and drug toxicity are two crucial problems. The recent advances in bioinformatics, parasite genomics, and biochemistry methodologies are contributing to better understand parasite biology, which is essential to guide the development of new therapies. In this review, we present the efforts that are being made in the evaluation of mAbs for the prevention or treatment of leishmaniasis, Chagas disease, malaria, and toxoplasmosis. Particular emphasis will be placed on the potential strengths and weaknesses of biological treatments in the control of these protozoan diseases that are still affecting hundreds of thousands of people worldwide.

Dientamoebiasis is globally distributed and detected in a large number of subjects with diarrhea, abdominal discomfort, flatulence, fatigue and loss of appetite. The life cycle and transmission of Dientamoeba fragilis are poorly understood. Microscopic examination of permanent stained smears is traditionally employed to diagnose the infection. However, this approach is time-consuming and the success in detecting D. fragilis depends on the microscopist’s experience. Hence, only a few laboratories routinely carry out tests for D. fragilis. Consequently, the prevalence of D. fragilis infection is probably underestimated. Although novel, rapid and more sensitive diagnostic tests are becoming available for detecting intestinal parasites, they also possess some limitations. The aim of this study was to emphasize the importance of performing microscopic examination of permanent stained smears from at least one fresh stool specimen after sample arrival at the laboratory, as a mandatory practice for the diagnosis of dientamoebiasis, particulary where it is not possible to perform molecular assays.

Trichophyton rubrum and Trichophyton mentagrophytes spp. are two of the most frequently isolated dermatophytes causing dermatophytosis worldwide. Since the incidence of resistance to antifungal agents is increasing, antifungal susceptibility tests are needed to successfully treat dermatophytoses. Most of the methods currently available are complicated, time-consuming and lack of reference procedures. The aim of this work was to establish a simple protocol to test the susceptibility of dermatophytes isolated from clinical samples against five antifungal drugs using E-test and disk diffusion methods. We used the E-test on non-supplemented Mueller–Hinton agar plates to determine the minimum inhibitory concentrations (MICs) of fluconazole, itraconazole, voriconazole and amphotericin B, and disk diffusion method to determine the interpretive MIC of terbinafine. Fifty dermatophytes—10 T. rubrum and 40 T. mentagrophytes spp.—were assessed after only 96 h of colony growth. Terbinafine was the most active antifungal agent with an inhibition diameter greater than 70 mm (sensitivity > 20 mm), followed by voriconazole, itraconazole and amphotericin B with MICs ranging from 0.032 to 0.38 µg/mL, from 0.006 to 0.125 µg/mL and from 0.5 to 1.5 µg/mL, respectively. All isolates were resistant to fluconazole. Collectively, the less laborious E-test and disk diffusion method were shown to be suitable and reliable to determine antifungal sensitivity of dermatophytes. This simple standard protocol could be employed in the routine of clinical laboratories.

OBJECTIVE: The analysis of the protein pattern of Klebsiella pneumoniae carbapenemase (KPC)-producing strains by Bruker Matrix-Assisted Laser Desorption Ionization (MALDI) Biotyper system has revealed the presence, in the majority of cases, of an 11.109 m/z peak. The peak corresponds to the gene product named p019 of the bla(KPC)-bearing plasmids and has been suggested as a candidate for a biomarker that is able to distinguish KPC-producers from non-KPC-producers. The aim of this study was to evaluate the rapid detection of the 11.109 m/z peak of KPC-producer strains in the clinical laboratory routine by Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) technique, using the Vitek(®) Research-User-Only (RUO) Mass Spectrometry (MS) system without changing the instrument parameters. MATERIALS AND METHODS: Globally, 373 K. pneumoniae isolates were investigated and identified by MALDI-TOF MS analysis. KPC-producers were distinguished from non-KPC-producers by Antimicrobial Susceptibility Testing (AST) and phenotypic carbapenemase resistance assays. RESULTS: The MALDI-TOF Vitek MS RUO detected the 11.109 m/z peak in 95.7% of KPC-producers with 100% specificity before traditional test results became available. CONCLUSION: Our approach is appropriate as a first screening step for the rapid identification of KPC isolates, which will help to improve infection control in clinical practice and prevent the outbreak and dissemination of resistant bacteria.

Malaria infections due to the Plasmodium parasite remains a major global health problem. Plasmodium falciparum is responsible for majority of the severe cases, resulting in more than 400,000 deaths per annum . Extracellular vesicles (EVs) released by vascular cells, including parasitised erythrocytes, have been detected with increased levels in patients with malaria. EVs are thought to be involved in the pathogenesis of severe malaria, particularly cerebral malaria, and represent a unique molecular signature for different forms of the infection. In this review, we will cover the known effects of EVs on the vasculature and discuss their potential use as a biomarker of disease severity.

Background: No data are available on the frequency of organ-specific humoral autoimmunity at diagnosis of adult celiac disease (CD).Aim: To evaluate the humoral immunoreactivities specific of type ...

Background and Aims. Neurotensin (NT) is a gut hormone secreted by specific endocrine cells scattered throughout the epithelial layer of the small intestine, which has been identified as an important mediator in several gastrointestinal functions and disease conditions. Its potential involvement in celiac disease (CD) has been investigated, but there are conflicting findings. The aim of this study was to evaluate serum NT levels in children with CD at diagnosis, compared to a control group, and to investigate whether NT correlated in CD patients with symptoms, antibody response, and intestinal mucosal damage.Materials and Methods. Children (1-16 years old) undergoing gastrointestinal endoscopy for CD or for other clinical reasons were included in this study. Patients with CD diagnosed according to the 2012 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines without biopsy were also recruited. Fasting serum samples were analyzed for NT levels using ELISA. Logistic regression, Wilcoxon rank sum, and Spearman’s rank tests were used for statistical analysis.Results. Thirty children (18 females, 2.2-15.9 years old) were enrolled. Of 25 patients who underwent endoscopy, 9 were CD patients, 13 were controls, and 3 were excluded due to nonspecific inflammation at duodenal biopsy. CD was diagnosed in 5 patients without biopsy. NT median was higher in CD patients compared to controls (13.25 (IQR 9.4-17.5) pg/ml vs. 7.8 (IQR 7.6-10) pg/ml;p=0.02). No statistically significant association between NT and clinical, serological, or histological data of CD was observed in this CD cohort.Conclusions. To our knowledge, this is the first study that evaluates NT in CD children from Italy. Results show that NT is higher in the serum of CD children at diagnosis compared to controls. However, larger-scale studies are required to validate these findings. Whether serum NT levels can be an adjunctive marker for pediatric CD remains currently elusive.

The hepatokine fetuin-A might have a role as molecular link between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate the association between fetuin-A and the prevalence and severity of NAFLD in a population of young adults. Ninety-seven adults (age 35.7 ± 12.4 years, female 64.9%), enrolled in a previous study evaluating NAFLD prevalence in the presence or absence of family history of T2DM, were included. Serum levels of fetuin-A (ELISA BioVendor, Czech Republic) and the main biochemical parameters were assessed. Presence and severity of NAFLD were evaluated by ultrasonography (Toshiba, Japan). A linear regression was run to predict fetuin-A levels and a logistic regression was performed to predict moderate–severe steatosis. Fetuin-A associated inversely with age (s − 0.12, p = 0.03) and directly with body mass index (BMI) (s 0.5, p = 0.048), waist circumference (WC) (s 0.3, p = 0.027), triglycerides (TG) (s 0.1, p = 0.001) and uric acid (s 1.7, p = 0.018), after adjustment for age and sex. In a model including age, BMI, WC, TG and uric acid, age (s − 0.2, p = 0.002) and TG (s 0.04, p = 0.02) were independent predictors of fetuin-A. Prevalence of steatosis was 66%. The rates of mild and moderate–severe steatosis were 50.5% and 15.5%, respectively. In the logistic model, the independent predictors of moderate–severe steatosis were fetuin-A (OR 1.22, p = 0.036), age (OR 1.17, p = 0.01) and BMI (OR 2.75, p = 0.011). In a sample of young adults, circulating levels of fetuin-A correlated with moderate–severe NAFLD, independent of confounders, and with some metabolic parameters. Fetuin-A might be a useful marker to predict NAFLD and metabolic disorders.

Background: The reasons behind low adherence to the Mediterranean diet (Med-diet) are still not entirely known. We aimed to evaluate the effect of biological (i.e., sex-related) and psycho-socio-cultural (i.e., gender-related) factors on Med-diet adherence. Methods: Baseline Med-diet adherence was measured using a self-administered questionnaire among adults with ischemic heart disease (IHD) from the EVA (Endocrine Vascular Disease Approach) study. A multivariable analysis was performed to estimate the effect of sex- and gender-related factors (i.e., identity, roles, relations, and institutionalized gender) on low adherence. Results: Among 366 participants (66 ± 11 years, 31% women), 81 (22%) adults with low adherence demonstrated higher rates of diabetes, no smoking habit, lower male BSRI (Bem Sex Role Inventory) (median (IQR) 4.8 (4.1 to 5.5) vs. 5.1 (4.5 to 5.6) and p = 0.048), and higher Perceived Stress Scale 10 items (PSS-10) (median (IQR) 19 (11 to 23) vs. 15 (11 to 20) and p = 0.07) scores than those with medium-high adherence. In the multivariable analysis, only active smoking (odds ratio, OR = 2.10, 95% confidence interval, CI 1.14 to 3.85 and p = 0.017), PPS-10 (OR = 1.04, 95% CI 1.00 to 1.08, and p = 0.038) and male BSRI scores (OR = 0.70, 95% CI 0.52 to 0.95, and p = 0.021) were independently associated with low adherence. Conclusions: Male personality traits and perceived stress (i.e., gender identity) were associated with low Med-diet adherence regardless of the sex, age, and comorbidities. Therefore, gender-sensitive interventions should be explored to improve adherence in IHD.

Children with autism spectrum disorder (ASD) are characterized by difficulties in social cognition (SC) domains. The aim of this study is to build an SC network to explore associations among interacting elements within this cognitive construct. We used a graph analysis to explain how individual SC domains relate to each other and how these relations may differ between ASD and typically developing (TD) groups. Seventy-six children with ASD and 81 TD children, matched for verbal mental age, were subjected to three SC measures. Our results showed that TD children exhibited an SC network characterized by a single domain (i.e., social cognition), while children with ASD demonstrated communicating node communities where social information processing measured by the Social Information Processing Interview (SIPI) represents a key point in understanding network differences between groups.

Improvements in ischemic heart disease (IHD) management have been unbalanced between sexes, with coronary microvascular dysfunction considered the likely underlying reason. The Endocrine Vascular disease Approach (EVA) is an observational study (Clinicaltrial.gov NCT02737982) aiming to assess sex and gender interactions between coronary circulation, sexual hormones, and platelet function. Consecutive patients with IHD undergoing coronary angiography will be recruited: (1) to assess sex and gender differences in angiographic reperfusion indexes; (2) to evaluate the effects of estrogen/androgen on sex-related differences in myocardial ischemia; (3) to investigate the platelet biology differences between men and women with IHD; (4) to verify sex- and gender-driven interplay between response to percutaneous coronary intervention, platelets, sex hormones, and myocardial damage at baseline and its impact on 12-month outcomes. The integration of sex and gender in this translational project on IHD will contribute to the identification of new targets for further innovative clinical interventions.

The present study examined the extent to which individual differences in personality that have been previously associated with aggression in non-clinical subjects (Caprara et al., European Journal of Personality, 27(3), 290–303, 2013, Caprara et al., Developmental Psychology, 50(1), 71–85, 2014) account for aggression among adolescents referred to psychiatric services with diagnosis within the externalizing spectrum (i.e., conduct disorder, oppositional defiant disorder, and attention deficit hyperactivity disorder). In particular a conceptual model was examined in which individual differences in basic traits (i.e., emotional instability and agreeableness), lower order traits (i.e., irritability and hostile rumination), and social cognitive mechanisms (i.e., moral disengagement) account for aggressive behavior. One hundred and nine adolescents (81 males, 74.3%), ranging in age from 11 to 18 (M = 13.83, SD = 1.70) and referred to psychiatric services for the above diagnoses, participated at the study. Adolescents filled in questionnaires measuring the Big Five traits, as well as irritability, hostile rumination, and moral disengagement; their parents filled in the Child Behavior Checklist to assess children’s aggressive behavior. Findings corroborated the posited pattern of relations previously found in non-clinical samples. In accordance with those findings, moral disengagement largely mediated the association between traits and aggressive behavior. The model explained a significant portion of variance in aggressive behavior. As a novelty, findings showed a direct association between emotional instability and aggressive behavior, pointing to the major relevance of emotional disregulation in adolescents referred for externalizing problem behaviors in comparison to non-clinical adolescents.

BackgroundA substantial genetic component accounts for Autism Spectrum Disorders (ASD) aetiology, with some rare and common genetic risk factors recently identified. Large collections of DNAs from thoroughly characterized ASD families are an essential step to confirm genetic risk factors, identify new variants and investigate genotype-phenotype correlations. The Italian Autism Network aimed at constituting a clinical database and a biorepository of samples derived from ASD subjects and first-degree relatives extensively and consistently characterized by child psychiatry centers in Italy.MethodsThe study was approved by the ethical committee of the University of Verona, the coordinating site, and by the local ethical committees of each recruiting site. Certified staff was specifically trained at each site for the overall study conduct, for clinical protocol administration and handling of biological material. A centralized database was developed to collect clinical assessment and medical records from each recruiting site. Children were eligible for recruitment based on the following inclusion criteria: age 4–18 years, at least one parent or legal guardian giving voluntary written consent, meeting DSM-IV criteria for Autistic Disorder or Asperger’s Disorder or Pervasive Developmental Disorder NOS. Affected individuals were assessed by full psychiatric, neurological and physical examination, evaluation with ADI-R and ADOS scales, cognitive assessment with Wechsler Intelligence Scale for Children or Preschool and Primary, Leiter International Performance Scale or Griffiths Mental Developmental Scale. Additional evaluations included language assessment, the Krug Asperger’s Disorder Index, and instrumental examination such as EEG and structural MRI. DNA, RNA and plasma were collected from eligible individuals and relatives. A central laboratory was established to host the biorepository, perform DNA and RNA extraction and lymphocytes immortalisation. DiscussionThe study has led to an extensive collection of biological samples associated with standardised clinical assessments from a network of expert clinicians and psychologists. Eighteen sites have received ADI/ADOS training, thirteen of which have been actively recruiting. The clinical database currently includes information on 812 individuals from 249 families, and the biorepository has samples for 98% of the subjects. This effort has generated a highly valuable resource for conducting clinical and genetic research of ASD, amenable to further expansion.

© 2017 The Author(s). A systematic analysis of 240 causes of death in 2013 revealed that parasitic diseases were responsible for more than one million deaths. The vast majority of these fatalities resulted from protozoan infections presenting with neurological sequelae. In the absence of a vaccine, development of effective therapies is essential to improving global public health. In 2015, an intriguing strategy to prevent cerebral malaria was proposed by Gordon et al. 2015 mBio, 6:e00625. Their study suggested that inhibition of the mammalian target of rapamycin prevented experimental cerebral malaria by blocking the damage to the blood brain barrier and stopping the accumulation of parasitized red blood cells and T cells in the brain. Here, we hypothesize that the same therapeutic strategy could be adopted for other protozoan infections with a brain tropism, to prevent cerebral parasitosis by limiting pathogen replication and preventing immune mediated destruction of brain tissue.

Motivation A deleterious amino acid change in a protein can be compensated by a second-site rescue mutation. These compensatory mechanisms can be mimicked by drugs. In particular, the location of rescue mutations can be used to identify protein regions that can be targeted by small molecules to reactivate a damaged mutant. Results We present the first general computational method to detect rescue sites. By mimicking the effect of mutations through the application of forces, the double force scanning (DFS) method identifies the second-site residues that make the protein structure most resilient to the effect of pathogenic mutations. We tested DFS predictions against two datasets containing experimentally validated and putative evolutionary-related rescue sites. A remarkably good agreement was found between predictions and experimental data. Indeed, almost half of the rescue sites in p53 was correctly predicted by DFS, with 65% of remaining sites in contact with DFS predictions. Similar results were found for other proteins in the evolutionary dataset. Availability and implementation The DFS code is available under GPL at https://fornililab.github.io/dfs/ Supplementary information Supplementary data are available at Bioinformatics online.

OBJECTIVES Oral viscous budesonide is a recent therapeutic option for eosinophilic oesophagitis (EoE) compared with dietary restriction and inhaled steroids. This single-centre, open-label, not blinded study aims to evaluate the efficacy and safety of a new, preprepared oral viscous budesonide suspension (PVB) in children and adolescents with EoE. METHODS We treated 36 children with PVB (29 boys; median age 12 years) with EoE diagnosed according to European Society for Paediatric Gastroenterology Hepatology and Nutrition guidelines. Patients 150 cm height received 2 and 4 mg PVB daily, respectively, for 12 weeks. Upper gastrointestinal endoscopy was performed at baseline, after 12 weeks of therapy and 24 weeks after the end of therapy. Baseline and post-treatment scores were calculated for symptoms, endoscopy, and histology. Serum cortisol was performed at baseline, 12, and 36 weeks. RESULTS At the end of PVB trial, endoscopy showed macroscopic remission in 32 patients (88.9%), whereas at histology median pre- and post-treatment peak eosinophil count/high power field (HPF) markedly decreased from 42.2 (range: 15-100) to 2.9 (range: 0-30); moreover, mean symptom and histology scores impressively improved compared with baseline (P

Madagascar is a geographically isolated country considered a biodiversity hotspot with unique genomics. Both the low-income and the geographical isolation represent risk factors for the development of diabetes. During a humanitarian health campaign conducted in Ambanja, a rural city in the northern part of Madagascar, we identified 42 adult subjects with diabetes and compared their features to 24 randomly enrolled healthy controls. 42.9% (n=18) of diabetic subjects showed HbA1c values ≥ 9.0%. Unexpectedly, waist circumference and BMI were similar in people with diabetes and controls. Different from the healthy controls, diabetic subjects showed a low prevalence of obesity (5.7% versus 30%, p=0.02). Accordingly, we found a high prevalence of autoimmune diabetes as 12% of people with diabetes showed positivity for the autoantibody against glutamic acid decarboxylase. Diabetic subjects with positive autoantibody had higher HbA1c values (11.3 ± 4.1% versus 8.3 ± 2.6%, p=0.03) compared to diabetic subjects with negative autoantibody. In conclusion, here we describe the presence of diabetes and its features in a rural area of Northern Madagascar, documenting poor glycaemic control and a high prevalence of autoimmune diabetes. These data highlight that the diabetes epidemic involves every corner of the world possibly with different patterns and features.

Mutations resulting in amino acid substitution influence the stability of proteins along with their binding to other biomolecules. A molecular understanding of the effects induced by protein mutations are both of biotechnological and medical relevance. The availability of empirical free energy functions that quickly estimate the free energy change upon mutation (ΔΔG) can be exploited for systematic screenings of proteins and protein complexes. Indeed,in silicosaturation mutagenesis can guide the design of new experiments or rationalize the consequences of already-known mutations at the atomic level. Often software such as FoldX, while fast and reliable, lack the necessary automation features to make them useful in high-throughput scenarios. Here we introduce MutateX, a software which aims to automate the prediction of ΔΔGs associated with the systematic mutation of each available residue within a protein or protein complex to all other possible residue types, by employing the FoldX energy function. MutateX also supports ΔΔG calculations over protein ensembles and the estimation of the changes in free energy upon post-translational modifications. At the heart of MutateX lies an automated pipeline engine that handles input preparation, performs parallel runs with FoldX and outputs publication-ready figures. We here illustrate the MutateX protocol applied to the study of the mutational landscape of cancer-related proteins, industrial enzymes and protein-protein interfaces. The results of the high-throughput scan provided by our tools could help in different applications, such as the analysis of disease-associated mutations, or in the design of protein variants for experimental studies or industrial applications. MutateX is a collection of Python tools that relies on Open Source libraries and requires the FoldX software to be installed beforehand. It is available free of charge and under the GNU General Public License fromhttps://github.com/ELELAB/mutatex.

Objective Almost 6% of celiac disease (CD) patients at diagnosis are positive for at least one of the main pancreatic islet autoantibodies that characterize type 1 diabetes (T1D). Few information, dated back to almost two decades ago, exist as to whether a gluten-free diet (GFD) could reduce the islet-specific autoimmunity detected in patients at CD diagnosis. Aim of the study was to evaluate the impact of GFD on 31 patients who presented islet-specific autoimmunity at CD diagnosis. Methods CD patient sera collected at diagnosis and throughout the GFD were analyzed for the main humoral autoantibodies so far identified in T1D, directed against one or more among insulin, glutamic-acid decarboxylase, tyrosine-phosphatase 2, and zinc cation-efflux transporter autoantigens. Results GFD (median duration 39 months) was associated to a decrease or disappearance of the islet-specific autoantibodies in 71% of CD patients. Almost 80% of the patients who became autoantibody-negative during the GFD were positive for only one of the islet-specific autoimmune markers at CD diagnosis, with none of them developing diabetes. Conversely, 80% of the CD patients positive at diagnosis for ≥2 islet-specific autoantibodies were still positive after more than two years of GFD, with 25% of them developing T1D. Conclusions Various factors appear to influence, individually or in combination, the effects of the GFD on pancreatic islet-specific autoimmune response detected at CD diagnosis. These factors include the number of diabetes autoantibodies found at CD diagnosis, the adherence to the GFD, its duration and an asymptomatic clinical presentation of CD.

BACKGROUND: The safety and efficacy of aspirin for the primary prevention of cardiovascular disease in patients with diabetes mellitus remains controversial. DESIGN: A meta-analysis to investigate the effects of aspirin for the prevention of cardiovascular disease in diabetes mellitus. METHODS: Ten randomized controlled trials were selected using MEDLINE, EMBASE and CENTRAL databases until 27 September 2018. Risk ratios (RRs) with 95% confidence intervals (CIs) and risk differences (RDs) reported as incident events per 1000 person-years were calculated. RESULTS: In 33,679 patients, aspirin did not significantly reduce the risk of major adverse cardiovascular outcomes (RR 0.93, 95% CI 0.87–1.00, P = 0.06; RD −0.68 incident cases per 1000 person-years (95% CI −1.54, 0.17)), cardiovascular mortality (RR 0.95, 95% CI 0.83–1.09, P = 0.49; RD 0.11 incident cases per 1000 person-years (95% CI −0.80, 1.02)), myocardial infarction (RR 0.91, 95% CI 0.75–1.11, P = 0.36; RD −0.66 incident cases per 1000 person-years (95% CI −2.07, 0.75)), or stroke (RR 0.91,95% C, 0.76–1.10, P = 0.33; RD −0.55 incident cases per 1000 person-years (95% CI −1.57, 0.47)). There was a significantly higher risk of total bleeding associated with aspirin (RR 1.29, 95% CI 1.07–1.55, P = 0.01; RD 1.49 incident cases per 1000 person-years (95% CI 0.36, 2.61)). CONCLUSION: The use of aspirin for primary prevention of cardiovascular disease in patients with diabetes mellitus increases the risk of total bleeding without reducing the risk of major adverse cardiovascular outcomes.