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Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammation-mediated disease of the nasal mucosa and paranasal sinuses that often coexists with asthma. The role of atopy in the development and severity of CRSwNP is still a controversial issue. Objective: The aim of our study was to propose a systematic allergy workup to identify atopic patients in the context of CRSwNP and to characterize their allergen sensitization profile (sources/molecules). Methods: Patients with a diagnosis of CRSwNP (n = 97) were studied in the otorhinolaryngologist and allergy settings. Demographic and clinical data were collected for each patient. Different allergen sensitization profiles (sources/molecules) were evaluated in atopic CRSwNP patients by using component-resolved diagnosis (CRD). Results: In our cohort of patients, the CRSwNP was frequently diagnosed during adulthood with significant impact on health-related quality of life. Asthma and atopy were the most common comorbidities with a prevalence of asthma in the atopic group. In CRSwNP patients sensitized to grass pollens and/or to house dust mites, the CRD analysis revealed a prevalence of sensitization to species-specific allergens of Phleum pratense (Phl p1, Phl p2, and Phl p5) or Dermatophagoides pteronyssinus (Der p1 and Der p2) rather than to cross-reactive ones. Conclusion: To define the allergen sensitization profile in atopic CRSwNP patients by CRD, it may be useful to better characterize type 2 inflammation, thus providing a personalized endotype-driven treatment.

Background: Although liver biopsy remains the gold standard for the diagnosis and the monitoring of liver disease, non-invasive biomarkers have been recently suggested to predict liver disease severity, progression, and response to therapy. We investigated multiple tissue and circulating markers of angiogenesis in predicting the severity of biopsy-validated chronic liver diseases in patients with chronic hepatitis C virus (HCV) and in NAFLD/NASH patients. Methods: We studied samples from forty-six patients with HCV and/or NAFLD who underwent liver biopsy, liver ultrasonography, and liver stiffness measurement. Ishak and Brunt scores were calculated. Expression of selective genes and luminex analyses of 17 different circulating pro-angiogenic factors were performed. Results: The phenotype of NAFLD/NASH or HCV subjects was similar, except for insulin, which was expressed at higher levels in NAFLD/NASH patients. A Mann–Whitney test showed significant differences for the circulating levels of HB-EGF and for follistatin between HCV and NAFLD/NASH patients. In HCV patients, we found an inverse correlation between disease stage and BMP-9 and VEGF-A circulating levels, while in NASH/NAFLD direct correlations between stage and BMP-9 and VEGF-A circulating levels were noted. The K-means algorithm divided HCV and NASH/NAFLD patients in two clusters with significant differences between them. Logistic regression models showed a positive relationship with BMP-9 levels for NASH/NAFLD and with HB-EGF circulating concentrations for HCV. ROC analysis showed for BMP-9 > 1188 pg/mL a worse disease in NASH/NAFLD, whereas for HB-EGF < 61 pg/mL a higher severity of disease in HCV. Conclusion: Our data show that circulating biomarker profiles can identify the severity of chronic liver disease of NAFLD/NASH or HCV origin.

Population genetic studies provide accurate information on population structure, connectivity, and hybridization. These are key elements to identify units for conservation and define wildlife management strategies aimed to maintain and restore biodiversity. The Mediterranean island of Sardinia hosts one of the last autochthonous mouflon populations, descending from the wild Neolithic ancestor. The first mouflon arrived in Sardinia ~ 7000 years ago and thrived across the island until the twentieth century, when anthropogenic factors led to population fragmentation. We analysed the three main allopatric Sardinian mouflon sub-populations, namely: the native sub-populations of Montes Forest and Mount Tonneri, and the reintroduced sub-population of Mount Lerno. We investigated the spatial genetic structure of the Sardinian mouflon based on the parallel analysis of 14 highly polymorphic microsatellite loci and mitochondrial D-loop sequences. The Montes Forest sub-population was found to harbour the ancestral haplotype in the phylogeny of European mouflon. We detected high levels of relatedness in all the sub-populations and a mitochondrial signature of hybridization between the Mount Lerno sub-population and domestic sheep. Our findings provide useful insights to protect such an invaluable genetic heritage from the risk of genetic depletion by promoting controlled inter-population exchange and drawing informed repopulation plans sourcing from genetically pure mouflon stocks.

International audience; ZUSAMMENFASSUNG ‘Die Toten beobachten uns’: Eine Landschaftsstudie der vorgeschichtlichen Felsengrabfriedhöfe in Ossi, Sardinia, Italy , von Guillaume Robin, Florian Soula, Pascal Tramoni, Laura Manca, und Kirsty Lilley Die Insel Sardinien ist bekannt für ihre unterirdischen Felsengräber des Spätneolithikums und der Kupferzeit, die über Generationen für Kollektivbestattungen genutzt wurden. Viele Gräber waren derart dekoriert, dass sie dem Inneren von Häusern glichen, und die Friedhöfe werden oft als Dörfer der Toten angesprochen. Die bisherige Forschung konzentrierte sich auf die Ausgrabung von stratigraphischen Kontexten innerhalb einiger dieser Monumente oder auf typologische Klassifizierungen von Grabplänen und Wanddekorationen, aber der landschaftliche Kontext der Friedhöfe und ihre Beziehung zu Siedlungen wurden übersehen. Der Artikel stellt die Ergebnisse von zwei Surveykampagnen in Ossi (Nordwestsardinien) vor, die sich auf zwei große Friedhöfe (Mesu ‘e Montes und S’Adde ‘e Asile) konzentrieren. Durch die Kombination von Feldbegehung, Kartierung und 3D-Aufnahmeverfahren liefern die Surveys eine umfassende Dokumentation der Friedhöfe (von der unterirdischen Architektur einzelner Gräber bis zu ihrem landschaftlichen Umfeld) und ergeben Hinweise auf prähistorische Siedlungen in ihrer Umgebung. Der Artikel diskutiert die topographischen und visuellen Beziehungen zwischen den Gräbern und den Wohngebieten und wie sie möglicherweise die sozialen Interaktionen zwischen den Lebenden und den Toten in Sardinien während der jüngeren Vorgeschichte widerspiegeln.; The island of Sardinia is well known for its Late Neolithic and Copper Age underground rock-cut tombs that were used over generations for collective burials. Many tombs were decorated to resemble house interiors and cemeteries are often referred to as villages of the dead. Research so far has focused on excavating stratigraphic contexts within some of these monuments, or on typological classifications of tomb plans and wall decorations, but the landscape context of the cemeteries and their relationship to settlements have been overlooked. The article presents the results of two seasons of survey in Ossi (north-west Sardinia), focusing on two major cemeteries (Mesu ‘e Montes and S’Adde ‘e Asile). Combining fieldwalking, mapping and 3D recording techniques, the survey provides a comprehensive documentation of the cemeteries (from the underground architecture of individual tombs to their landscape setting) and yields evidence of prehistoric settlements in their vicinity. The article discusses the topographic and visual relationships between the tombs and the residential areas and how they may reflect social interactions between the living and the dead in late prehistoric Sardinia.; RESUMEN “Los muertos nos están mirando”: un estudio de paisaje de los cementerios prehistóricos con tumbas excavadas en la roca en Ossi, Cerdeña, Italia , por Guillaume Robin, Florian Soula, Pascal Tramoni, Laura Manca, y Kirsty Lilley La isla de Cerdeña es muy conocida por las tumbas excavadas en la roca adscritas al Neolítico final y la Edad del Bronce que fueron utilizadas durante generaciones como enterramientos colectivos. Muchas de estas tumbas fueron decoradas para parecerse a los interiores de las casas y los cementerios a menudo se conocen como las villas de los muertos. Hasta ahora la investigación se ha centrado en la excavación de contextos estratigráficos dentro de estos monumentos, así como en la clasificación tipológica de las plantas de las tumbas y de las decoraciones de las paredes, sin embargo, el contexto paisajístico de los cementerios y su relación on los asentamientos ha sido ignorado. El artículo presenta los resultados de las campañas de prospección en Ossi (noroeste de Cerdeña), centradas en dos cementerios de gran tamaño (Mesu ‘e Montes and S’Adde ‘e Asile). Los trabajos de prospección, combinando prospección superficial, mapeado y técnicas de registro 3D, aportan una documentación completa de los cementerios (desde la arquitectura subterránea de las tumbas individuales a su entorno paisajístico) y evidencias de los asentamientos prehistóricos de su entorno. El artículo discute las relaciones topográficas y visuales entre las tumbas y las áreas residenciales y cómo podrían estar reflejando interacciones sociales entre la vida y la muerte de la Prehistoria reciente de Cerdeña.; RÉSUMÉ ‘Les morts nous regardent’: Etude du paysage des cimetières nécropoles à tombes hypogées préhistoriques à Ossi, Sardaigne, Italie, de Guillaume Robin, Florian Soula, Pascal Tramoni, Laura Manca, et Kirsty Lilley L’île de la Sardaigne est renomée pour ses tombes souterraines taillées dans le rocher du Néolithique final et de l’âge du cuivre qui furent utilisées pendant des générations pour des inhumations collectives. Nombre de ces tombes étaient décorées de manière à ressembler à des intérieurs de maisons et les nécropoles sont souvent présentées comme aux villages des morts. Les recherches se sont, jusqu’à présent concentrées sur la fouille des contextes stratigraphiques à l’intérieur de certains de ces monuments ou sur la classification typologique des plans de tombes et des décorations murales mais le contexte du paysage de ces cimetières et leurs relations avec les habitats ont été négligés. Les résultats de deux campagnes de prospections à Ossi, nord ouest de la Sardaigne, se concentrant sur deux importantes nécropoles (Mesu ‘e Montes et S’Adde ‘e Asile). Associant prospections pédestres, géolocalisation, et techniques de relevés 3D, l’etude de terrain fournit une documentation détaillée des nécropoles qui va de l’architecture souterraine de tombes individuelles à leur situation dans le paysage et a relevé des témoinages d’occupations préhistoriques à proximité. Cet article discute les relations topographiques et visuelles entre les tombes et les zones habitées et comment elles pouvaient refléter les interactions entre les vivants et les morts à la fin de la Prehistoire en Sardaigne.

COVID-19 is a respiratory-centered systemic disorder caused by SARS-CoV-2. The disease can progress into a severe form causing acute lung injury.CD48 is a co-signaling receptor, existing as both membrane-bound and soluble forms reported to be dysregulated in several inflammatory conditions. Therefore, we reasoned that CD48 could be deregulated in COVID-19 as well.Here we analyzed CD48 expression in autoptic sections and peripheral blood leukocytes and sera of COVID-19 patients by gene expression profiling (HTG® autoimmune panel), immunohistochemistry, flow cytometry and ELISA.Lung tissue of COVID-19 patients showed increased CD48 mRNA expression and infiltration of CD48+ lymphocytes. In the peripheral blood, mCD48 was considerably increased on all evaluated cells, and additionally, sCD48 levels were significantly higher in COVID-19 patients independently of disease severity. Considering the alterations of mCD48 and sCD48, a specific role for CD48 in COVID-19 can be assumed, suggesting it as a potential target for therapy.

BackgroundSLE is an autoimmune disease that predominantly affects women. As most epidemiological and interventional studies are on populations with a clear female prevalence, the influence of gender in disease course, drug response and damage accrual is yet to be fully explored and comprehended.ObjectivesTo describe gender differences in disease course, comorbidities, use of medications and long-term outcomes of a large cohort of patients with SLE.MethodsRetrospective gender-based analysis of prospectively collected data from a monocentric cohort of Caucasian patients with SLE with at least 1 year of follow-up.Results417 patients were included, 51 men and 366 women. Men displayed a significantly higher median age at disease onset and diagnosis and a higher prevalence of late-onset SLE, serositis at disease onset, antiphospholipid syndrome (APS) and use of mycophenolate within the first year of disease. Women had a higher prevalence of haematological abnormalities, a higher cumulative exposure to azathioprine and higher cumulative dose of glucocorticoids at 5 years. Male patients had a shorter time to first damage item and a higher prevalence of damage at 1 and 5 years, but this association was no longer significant when late-onset patients were excluded. No differences were found in prevalence of childhood onset, delay between onset and diagnosis, time to renal involvement and histology, cumulative autoantibody positivity, number of flares and hospitalisations, median SLE Damage Index score, type of damage, age and time to first cardiovascular event, chronic kidney disease and death.ConclusionsIn our cohort, clinical manifestations and disease course were similar in male and female patients; however, male patients displayed higher prevalence of APS and early damage accrual probably due to the later disease onset. These data highlight the importance of an intensive follow-up, prevention and treatment of complications in this category of patients, especially in the first years of disease.

BackgroundProteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms.AimWe aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits.Materials and MethodsThe CAPIRE study (ClinicalTrials.gov Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45–75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD+) or completely clean arteries (CAD−) and either ≤ 1 risk factor (RF+) or ≥3 risk factors (RF−) (based on history, blood pressure, glycemia, lipids, and smoking).ResultsOf 544 individuals, 39% were atypical (93 CAD+/RF−; 120 CAD−/RF+) and 61% typical (102 CAD+/RF+; 229 CAD−/RF−). In the comparison with CAD+/RF− adjusted for sex and age, CAD−/RF+ was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUCROC's of 0.72–0.81 (overall p = 1.0e−38). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA1c, and smoking.ConclusionsIn a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA1c. These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can progress into a severe form of acute lung injury. The cosignaling receptor cluster of differentiation 48 (CD48) exists in membrane-bound (mCD48) and soluble (sCD48) forms and has been reported to be implicated in antiviral immunity and dysregulated in several inflammatory conditions. Therefore, CD48 dysregulation may be a putative feature in COVID-19-associated inflammation that deserves consideration.To analyze CD48 expression in lung autopsies and peripheral blood leukocytes and sera of patients with COVID-19. The expression of the CD48 ligand 2B4 on the membrane of peripheral blood leukocytes was also assessed.Twenty-eight lung tissue samples obtained from COVID-19 autopsies were assessed for CD48 expression using gene expression profiling immunohistochemistry (HTG autoimmune panel). Peripheral whole blood was collected from 111 patients with COVID-19, and the expression of mCD48 and of membrane-bound 2B4 was analyzed by flow cytometry. Serum levels of sCD48 were assessed by enzyme-linked immunosorbent assay.Lung tissue of patients with COVID-19 showed increased CD48 messenger RNA expression and infiltration of CD48+ lymphocytes. In the peripheral blood, mCD48 was considerably increased on all evaluated cell types. In addition, sCD48 levels were significantly higher in patients with COVID-19, independently of disease severity.Considering the changes of mCD48 and sCD48, a role for CD48 in COVID-19 can be assumed and needs to be further investigated.

Simple Summary The development of hypersensitivity reactions to platinum agents in patients with gynecological cancers limits the use of platinum re-treatment for recurrent disease. In those patients who developed a hypersensitivity reactions during treatment with platinum agents it could be safer to undergo allergy diagnosis. This approach includes the in-vivo skin tests before re-exposure to the platinum agent, especially in those patients who have to undergo a 2nd or 3rd line therapy. In our experience, skin test for platinum agents resulted in a simple and sensitive tool for the diagnosis and prevention of hypersensitivity reactions to platinum agents. In addition, this approach identified a sub-group of patients that became sensitized to the platinum agent during the previous platinum-based therapy. Abstract Background: Hypersensitivity reactions (HSR)s to platinum agents are increasing in frequency, due to their extensive use and repeated exposures in patients with increased life expectancy. The aims of our study are to analyze the frequency of both type I and type IV HSRs in patients with gynecological cancer treated with (CBDCA) carboplatin and/or (CDDP) cisplatin, to evaluate the role of skin tests in the diagnosis and prevention of HSRs. Methods: From 2011 to 2018, we evaluated 124 consecutive female patients previously treated with CBDCA and/or CDDP for gynecological cancer. All patients, including those with and without HSR to previous platinum-based therapy, underwent in-vivo skin tests for platinum agents before starting the second or more therapeutic lines. To reduce the risk of false negative results, patients with a negative skin test at the first evaluation were re-tested after 3 weeks from the platinum re-exposure. Results: Among the 124 patients evaluated, 58 (47%) experienced HSRs to at least one platinum agent: 35% were to CBDCA, 5% to CDDP, 7% to both. Fifty-six of the 58 HSRs were classified as immediate and two delayed. Skin tests confirmed an IgE-dependent mechanism in 67% of patients with immediate-HSRs to CBDCA and identified a cross-reactivity between platinum agents in 18% of patients. Moreover, among those who had never developed an HSRs during platinum-based therapy, in-vivo skin tests identified 12% of sensitized patients. Conclusions: On the basis of our findings, skin test for platinum agents is a simple and sensitive tool for the diagnosis and prevention of HSRs to CBDCA and/or CDDP and can be useful for detecting possible cross-reactivity among platinum agents.

Human activities are having increasingly devastating effects on the health of marine and terrestrial ecosystems. Studying the adaptive responses of animal species to changes in their habitat can be useful in mitigating this impact. Vultures represent one of the most virtuous examples of adaptation to human-induced environmental changes. Once dependent on wild ungulate populations, these birds have adapted to the epochal change resulting from the birth of agriculture and livestock domestication, maintaining their essential role as ecological scavengers. In this review, we retrace the main splitting events characterising the vultures’ evolution, with particular emphasis on the Eurasian griffon Gyps fulvus. We summarise the main ecological and behavioural traits of this species, highlighting its vulnerability to elements introduced into the habitat by humans. We collected the genetic information available to date, underlining their importance for improving the management of this species, as an essential tool to support restocking practices and to protect the genetic integrity of G. fulvus. Finally, we examine the difficulties in implementing a coordination system that allows genetic information to be effectively transferred into management programs. Until a linking network is established between scientific research and management practices, the risk of losing important wildlife resources remains high.

Observers are better at discriminating upright bodies than inverted bodies, and this body inversion effect (BIE) is reliable with whole figures (bodies with heads), but not with bodies presented without heads or the heads occluded suggesting that heads may be key to BIEs. Some studies present whole figures and bodies without heads between groups, and BIEs are not found for bodies without heads [1]. Other studies present whole figures and bodies without heads in the same blocks and BIEs are found with bodies without heads [2]. Does seeing the heads of whole figures induce BIEs in bodies without heads? Here, participants discriminated bodies with either whole figures and bodies without heads presented within blocks, or in separate blocks with bodies without heads presented first. We tested body identity and posture discrimination and measured participants’ gaze. BIEs were found with whole figures and bodies without heads in both identity and posture discrimination, and in both study designs. However, efficiency scores were better for the whole figures than the bodies without heads, but only when whole figures appeared in separate blocks. The magnitude of the BIE was overall stronger for whole figures compared to bodies without heads, but only in identity discrimination. BIE magnitudes were similar in the identity and posture tasks. Participants were better at identity discrimination, yet, there was greater looking at heads and less at bodies. During posture discrimination, greater looking at bodies and less at heads was associated with better performance. Faces might influence BIEs but are not essential. Configural representations of bodies without heads are sufficient for BIEs in posture and identity discrimination.

Background: Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration. Objective: The current study aimed to investigate the diagnostic value of total α-syn, amyloid-β (Aβ1–42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer’s disease (AD) patients compared to healthy controls (HC). Methods: By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aβ1–42, tau, and their heteroaggregates (α-syn/Aβ1–42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson’s disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60). Results: The total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in the LBD group and the AD group compared with HC, whereas α-syn/Aβ1–42 concentrations were significantly lower in the AD dementia group only. RBC α-syn/tau heterodimers had a higher diagnostic accuracy for differentiating patients with LBD versus HC (AUROC = 0.80). Conclusion: RBC α-syn heteromers may be useful for differentiating between neurodegenerative dementias (LBD and AD) and HC. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBD from HC. However, they are not consistently different between LBD and AD. Our findings also suggest that α-syn, Aβ1–42, and tau interact in vivo to promote the aggregation and accumulation of each other.

Background Chronic kidney disease (CKD) shows different clinical features in Types1 (T1D) and 2 diabetes (T2D). Metabolomics have recently provided useful contribution to the identification of biomarkers of CKD progression in either form of the disease. However, no studies have so far compared plasma metabolomics between T1D and T2D in order to identify differential signatures of progression of estimated glomerular filtration rate (eGFR) decline. Methods We used two large cohorts of T1D (from Finland) and T2D (from Italy) patients followed up to 7 and 3 years, respectively. In both groups, progression was defined as the top quartile of yearly decline in eGFR. Pooled data from the two groups were analysed by univariate and bivariate random forest (RF), and confirmed by bivariate partial least squares (PLS) analysis, the response variables being type of diabetes and eGFR progression. Results In progressors, yearly eGFR loss was significantly larger in T2D [−5.3 (3.0), median (interquartile range)mL/min/1.73 m2/year] than T1D [−3.7 (3.1) mL/min/1.73 m2/year ; P = 0.018]. Out of several hundreds, bivariate RF extracted 22 metabolites associated with diabetes type (all higher in T1D than T2D except for 5-methylthioadenosine, pyruvate and β-hydroxypyruvate) and 13 molecules associated with eGFR progression (all higher in progressors than non-progressors except for sphyngomyelin). Three of the selected metabolites (histidylphenylalanine, leucylphenylalanine, tryptophylasparagine) showed a significant interaction between disease type and progression. Only eight metabolites were common to both bivariate RF and PLS. Conclusions Identification of metabolomic signatures of CKD progression is partially dependent on the statistical model. Dual analysis identified molecules specifically associated with progressive renal impairment in both T1D and T2D.

ObjectivesIn patients with systemic autoimmune rheumatic disorders (SARDs), vaccination with SARS-CoV-2 mRNA vaccines has been proposed. The aim of this study is to evaluate the immune response elicited by vaccination with mRNA vaccine, testing IgM, IgA and IgG antibodies to SARS-CoV-2 receptor-binding domain (RBD) and measuring neutralising antibodies.MethodsIgG, IgM and IgA anti-RBD antibodies were measured in 101 patients with SARDs. Antibodies inhibiting the interaction between RBD and ACE2 were evaluated. Antibody avidity was tested in a chaotropic ELISA using urea. Twenty-one healthcare workers vaccinated with mRNA vaccine served as control group.ResultsAnti-RBD IgG and IgA were produced after the first dose (69% and 64% of the patients) and after the boost (93% and 83%). Antibodies inhibiting the interaction of RBD with ACE2 were detectable in 40% of the patients after the first dose and 87% after boost, compared with 100% in healthy controls (pConclusionsThese data show that double-dose vaccination induced in patients with SARDs anti-RBD IgG and IgA antibodies in amounts not significantly different from controls, and, most interestingly, characterised by high avidity and endowed with neutralising activity.

International audience

To evaluate the functional and oncologic outcomes of adjuvant (chemo)radiation [(C)RT] after open partial horizontal laryngectomies (OPHLs). Multicenter retrospective evaluation of 130 patients (116 males, 14 females) submitted between 1995 and 2017 to OPHL Types II and III for laryngeal cancer and receiving adjuvant (C)RT for one or more of the following risk factors at histopathologic examination of the surgical specimen: pT4a and/or > pN2a categories, close/positive resection margins, or presence of both perineural (PNI) and lympho-vascular invasion (LVI). The primary study endpoints were evaluation of the presence of tracheostomy and/or gastrostomy at last follow-up, and calculation of laryngo-esophageal dysfunction-free survival (LEDFS). Mean age of the study cohort was 60.8 ± 8.9 years (median, 62; interquartile range [IQR], 13). Mean follow-up was 50.7 ± 39.4 months (range 24–188; median, 38; IQR, 51). Adjuvant therapy consisted of CRT in 53 (41%) patients, and RT alone in 77 (59%). Five-year LEDFS was 85%. Overall survival was 71.5%, while 13% of patients remained tracheostomy- and 3% gastrostomy-dependent at the last follow-up. The only significant variable in predicting survival (p = 0.020) was tracheostomy dependence: it was maintained in 7.5% of subjects after OPHL Type II and in 34% of those submitted to OHPL Type III (p

Background: Based on data from the Ministry of Health, which highlighted the earlier onset of Covid-19 epidemic in Italy, compared with the Europe, we would like to present a statistical elaboration on the impact of measures taken by the Government, during the phase 1 and the start of phase 2. Methods: After the implementation of a Bayesian changepoint detection method, we looked for a best fit model, based on the first part of time series data, in order to observe the progress of the data in the presence and absence of the restriction measures introduced. Results: Both the implementation of changepoint detection method and the analysis of the curves showed that the decree that marked the start of lockdown has had the effect of slowing down the epidemic by allowing thestart of a plateau between 21 and 25 March. Moreover, the decree that decided the beginning of phase 2 on 4 May did not have a negative impact. Conclusion: This statistical analysis supports the hypothesis that stringent measures decreased hospitalization, thanks to a slowing down in the evolution of the epidemic compared with what was expected.

Although mild traumatic brain injury (MTBI) in people on oral anticoagulant treatment (OAT) is a frequent challenge for Emergency Department (ED), strong guidelines recommendations are lacking. In the attempt to assess the safety profile of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs), we have recruited 473 patients with a MTBI on OAT (43.6% males; age 81.8 ± 8.7 years), admitted to the Pisa’s University Hospital ED (Jan 2016—Oct 2018). All patients underwent a head CT scan with those with no sign of acute bleedings remaining under clinical observation for the ensuing 24 h. Fifty patients (10.6%, 95% CI: 8.1–13.7%) had immediate intracranial hemorrhage (ICH), with a prevalence of patient-important outcomes due to immediate ICH of 1.1% (95% CI 0.4–2.4%); 3 patients died (0.6%, 95% CI 0.2–1.8) and 2 required neurosurgical intervention. Immediate ICHs were more frequent in VKA-treated than in DOAC-treated patients (15.9 vs. 6.4%. RR 2.5. 95%CI 1.4–4.4. p

Highlights • Subjects with obesity affected by COVID-19 require longer hospitalization compared to subjects without obesity. • Subjects with obesity require more time to clear from SARS-COV-2 shedding compared to subjects without obesity. • Subjects with obesity affected by COVID-19 have higher inflammatory markers compared to subjects without obesity., Introduction On the last three months the new SARS-COV-2 coronavirus has created a pandemic, rapidly spreading all around the world. The aim of the study is to investigate whether obesity impacts on COVID-19 morbidity. Methods One hundred consecutive patients with COVID-19 pneumonia admitted in our Medical Unit were evaluated. Anthropometric parameters and past medical history were registered. Nasopharyngeal swab samples and biochemical analysis were obtained at admission and during hospital stay. Results Patients with (OB, 29) and without obesity (N-OB, 71) were similar in age, gender and comorbidities, with the exception of hypertension that was more frequent in OB group. At admission, inflammatory markers were higher in OB than N-OB group. OB group showed a worse pulmonary clinical picture, with lower PaO2 (57 ± 15 vs. 68 ± 14 mmHg, p = 0.042), and SaO2 (88 ± 6 vs. 92 ± 5%, p = 0.049) at admission consequently requiring higher volumes of oxygen (Fi02: 38 ± 15 vs. 29 ± 19%, p = 0.047) and a longer period to achieve oxygen weaning (10 ± 6 vs. 15 ± 7 days, p = 0.03). OB group also had positive swabs for longer time (19 ± 8 vs. 13 ± 7, days, p = 0.002), and required longer hospital stay (21 ± 8 vs. 13 ± 8, days, p = 0.0008). Partial least square regression analysis showed that BMI, age and CRP at admission were related to longer length of hospital stay, and time for negative swab. On the contrary, in this cohort, obesity did not predict higher mortality. Conclusions Subjects with obesity affected by COVID-19 require longer hospitalization, more intensive and longer oxygen treatment, and they may have longer SARS-COV-2 shedding.

Background Red blood cells (RBC) account for more than 99% of α-syn concentrations in blood representing an interesting in vivo model for studying peripheral pathological alterations proved in neurodegeneration. The aim of the current study was to investigate the diagnostic value of total α-syn, Aβ 1-42 , tau and their heteroaggregates in RBCs of Lewy Body Dementias (LBDs) and Alzheimer’s disease (AD) patients compared to and healthy controls (HCs). Methods With a “home-made” sandwich enzyme-linked immunosorbent assay (ELISA) system, RBCs levels of total α-syn, Aβ 1-42 , tau and their heteroaggregates (α-syn/Aβ 1-42 and α-syn/tau) were measured in 27 subjects with LBDs (PDD, n = 17; DLB, n = 10), 51 subjects with AD (AD dementia, n = 37, prodromal AD, n = 14), and HC (n = 60). Results Compared with HC, total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in LBDs group (p = 0.009, p = 0.009, and p < 0.001, respectively) and in AD group (p = 0.011, p = 0.003, and p < 0.001, respectively), whereas the heteroaggregates α-syn/Aβ 1-42 were significantly lower in AD dementia group (p < 0.001) only. RBC α-syn/tau heterodimers had the higher diagnostic accuracy for differentiating patients with LBD vs controls (AUROC = 0.80). Conclusion RBC α-syn heteroaggregates may be useful for differentiating between neurodegenerative dementias (LBD and AD) and healthy control. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBDs from HC. However, they are not consistently different between LBD and AD. Our findings also go beyond the clinical setting, suggesting that α-syn, Aβ 1-42 , and tau interact in vivo to promote the aggregation and accumulation of each other presumably accelerating cognitive dysfunction.

To assess the impact of bariatric surgery on remission and relapse of type 2 diabetes mellitus (T2DM) at 10 years of follow-up and analyze predictive factors.Eighty-eight obese subjects undergoing Roux-en-Y gastric bypass (RYGB) and 25 subjects assigned to medical therapy (MT) were evaluated every year for 10 years. T2DM remission was defined by the American Diabetes Association criteria.Body mass index (BMI), fasting glucose, and haemoglobin A1c (HbA1c) improved more markedly in RYGB than MT patients throughout the 10-year period. Post-surgery remission rates were 74% and 53% at 1 and 10 years, respectively, while remission did not occur in MT patients. One-year post-surgery, BMI decreased more in subjects with remission than in those without, but no further decrease was observed thereafter. By partial-least-squares analysis, T2DM duration, baseline HbA1c, and ensuing insulin therapy were the strongest predictors of remission. Remission was achieved at one year in 91% of patients with T2DM duration4 years, and 79% of them remained in remission at 10 years. On the contrary only 42% of patients with T2DM duration ≥ 4 years achieved remission, which was maintained only in 6% at the end of 10 years. By survival analysis, patients with T2DM duration4 years had higher remission rates than those with duration ≥ 4 years (hazards ratio (HR) 3.1 [95%CI 1.8-5.7]). Relapse did not occur before two years post-surgery and was much less frequent in patients with4- vs ≥ 4-year duration (HR 11.8 [4.9-29.4]).Short T2DM duration and good glycemic control before RYGB surgery were the best requisites for a long-lasting T2DM remission, whereas weight loss had no impact on the long-term relapse of T2DM.

In Italy the Eurasian griffon Gyps fulvus became extinct between the 19th and 20th centuries, with the exception of Sardinia where is now considered “critically endangered”. Here we provide the first whole mitogenome sequence of Gyps fulvus , which was 17,961 bp long. Evolutionary analysis pointed out a divergence between griffon and black vulture ( Aegypius monachus ) which occurred about 25.8 MYA, while the rise of the Gyps ancestor was dated back at around 5.4 MYA. In addition, the early radiation within the G . fulvus species started between 310 and 120 MYA. To prevent extinction of the Sardinian population, two restocking events were carried out, unfortunately without contributions of genetic evidences. To estimate the impact derived by the restocking activities, mitochondrial D-loop sequences from 22 museum individuals, which died before reintroduction events, were compared with 44 sequences from the extant population. Within the extant samples we detected three haplotypes (Hpt A, B and C). Hpt C showed the lowest frequency and it was not present among the museum samples, while Hpt A and B were found to be the most represented in extant and museum samples, respectively. In order to prevent the loss of genetic variability within the Sardinian population we recommend to refer to the new genetic information provided in the present study before the implementation of recovery programs in the future.

OBJECTIVE Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation—a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD− (clean coronaries) and CAD+ (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD. RESULTS Though CAD+ was more prevalent among participants with T2D (HbA1c 6.7 ± 1.1%) than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 2, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were “protected” from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02). CONCLUSIONS We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD.

The islands of Sardinia, Crete, and Cyprus are hosting the last native insular griffon populations in the Mediterranean basin. Their states have been evaluated from “vulnerable” to “critically endangered”. The sequence analysis of molecular markers, particularly the mtDNA D-loop region, provides useful information in studying the evolution of closely related taxa and the conservation of endangered species. Therefore, a study of D-loop region sequence was carried out to estimate the genetic diversity and phylogenetic relationship within and among these three populations. Among 84 griffon specimens (44 Sardinian, 33 Cretan, and 7 Cypriot), we detected four haplotypes including a novel haplotype (HPT-D) that was exclusively found in the Cretan population with a frequency of 6.1%. When considered as a unique population, haplotype diversity (Hd) and nucleotide diversity (π) were high at 0.474 and 0.00176, respectively. A similar level of Hd and π was found in Sardinian and Cretan populations, both showing three haplotypes. The different haplotype frequencies and exclusivity detected were in accordance with the limited matrilineal gene flow (FST = 0.07097), probably related to the species reluctance to fly over sea masses. The genetic variability we observe today would therefore be the result of an evolutionary process strongly influenced by isolation leading to the appearance of island variants which deserve to be protected. Furthermore, since nesting sites and food availability are essential elements for colony settlement, we may infer that the island's colonization began when the first domestic animals were transferred by humans during the Neolithic. In conclusion, our research presents a first contribution to the genetic characterization of the griffon vulture populations in the Mediterranean islands of Sardinia, Crete and Cyprus and lays the foundation for conservation and restocking programs.

Background European mouflon (Ovis orientalis musimon) has been reintroduced in mainland Europe since the 18th-century sourcing from the Sardinian and Corsican autochthonous mouflon populations. The European mouflon is currently considered the feral descendent of the Asian mouflon (O. orientalis), and the result of first wave of sheep domestication occurred 11,000 years ago in the Fertile Crescent, and brought to Corsica and Sardinia ca. 6,000 years ago, where they still live as autochthonous populations. However, this phylogeny is based on mitogenome sequences of European mouflon individuals exclusively. Methods We sequenced the first complete mtDNA of the long-time isolated Sardinian mouflon and compared it with several ovine homologous sequences, including mouflon from mainland Europe and samples representative of the five known mitochondrial domestic sheep haplogroups. We applied Bayesian inference, Maximum Likelihood and Integer Neighbour-Joining network methods and provided a robust, fully-resolved phylogeny with strong statistical support for all nodes. Results We identified an early split (110,000 years ago) of the Sardinian mouflon haplotype from both sheep and mainland European mouflon belonging to haplogroup B, the latter two sharing a more recent common ancestor (80,000 years ago). Further, the Sardinian mouflon sequence we generated had the largest genetic distance from domestic sheep haplogroups (0.0136 ± 0.004) among mouflon species. Our results suggest the Sardinian mouflon haplotype as the most ancestral in the HPG-B lineage, hence partially redrawing the known phylogeny of the genus Ovis.

We report a novelβ+-thalassemia mutation found in a Vietnamese family. The molecular defect T→A lies at -72 of theβ-globin gene promoter, within the conserved CCAAT box. The index case was a 5-year-old child having red blood cells indices close to normal and slightly increased level of HbA2(3.96%). The expression of the mutatedβallele was inferred by luciferase reporter assay in K562 cells. Theβ-72 determinant is the eighthβ-thalassemic mutation identified in Vietnam and it was not previously reported in any population. The absence of homozygous or compound heterozygous states did not allow us to precisely predict either its clinical impact or its relevance in management programs. Our results further underline the importance of identifying and characterizing new or rareβ+-thalassemic alleles in carrier screening and prenatal diagnosis.

Analyses of the Neolithic and Chalcolithic industry in hard animal material from the western Mediterranean include a rich corpus of studies focusing on osseous industries. However, studies relating to the shell industry mainly concentrate on the production of ornamental objects, and the overall background of this raw material for the production of utensils used for transformation activities is not yet well known. The technological analysis of the hard animal industry of Cuccuru S'Arriu (Cabras, Sardinia) discovered in Final Neolithic structures (4000-3500 BC) led to the identification of many sea shells collected for making artefacts, ornamental objects and utensils. This article focuses on the morphotechnological analysis of the Glycymeris da Costa, 1778 shells used as utensils, and the identification of artefact function. In particular, the experimental activities carried out for the analysis of use-wear traces are presented. These activities enhance our understanding of artefact functions (smo...

Aim of the present study is to compare the synchronization of the classical Kuramoto system and the reaction - diffusion space time Landau - Ginzburg model, in order to describe the alternation of REM (rapid eye movement) and NREM (non-rapid eye movement) sleep across the night. These types of sleep are considered as produced by the cyclic oscillation of two neuronal populations that, alternatively, promote and inhibit the REM sleep. Even if experimental data will be necessary, a possible interpretation of the results has been proposed.

In the above article, all mentions of “cartilage intermediate-layer protein” refer to “cartilage intermediate-layer protein 2.” The isoform number was misstated in the abstract and one place in the …

The study of the hard animal matter assemblage from Ali Tappeh Cave, located on the south-eastern shores of the Caspian Sea, sheds new light on many unknown aspects of Epipalaeolithic ways of life in this region and expands our knowledge of techno-economic strategies using materials other than lithic artefacts. Fourteen artefacts from the collection conserved in the National Museum of Iran were selected for the present research. The osseous and shell artefacts were studied using technological and microwear approaches in order to reconstruct the different stages of the techno-economic scheme of raw material acquisition, transformation and utilization of the objects. The technical marks show the use of abrasion, scraping and grooving techniques in the debitage and shaping phases for the transformation of bone tools, shell tools and ornaments. The acquisition and transformation sequences of the shell artefacts were partially reconstructed based on the identification of the finished objects, blanks, waste or potential rough-outs and raw material blocks. The acquisition sequence primarily focused on the collection of dead shells as raw material. The potential source of these materials, the south-eastern coast of the Caspian Sea, during the Epipalaeolithic was located about 40 km from the Ali Tappeh site. The choice of the blocks of raw materials only involves two species: Didacna and Cerastoderma. Three ways of raw material transformation were identified in this study: shell fracturing, probably connected to the production of discoid beads, direct shaping involving the regularization and perforation of elliptical raw material blocks for the production of pendants, direct shaping by perforating raw material blocks for the production of pendants. Suspension traces indicate their use as ornamental objects. Only one specimen in the whole assemblage was used directly, without prior transformation. The use-wear traces suggest the utilization of this shell tool for hide scraping. Similar processes are attested in some Epipalaeolithic sites in the Caucasus for the perforation of ornamental objects, suggesting analogous transformation methods for hard animal materials.

During a screening for hemoglobinopathies, we found a carrier of the Sardinian δβ-thalassemia condition. The proband's hematology and hemoglobin (Hb) profile agreed with those of the other carriers previously identified during our diagnostic program except for the fetal Hb (HbF) composition, which consisted of both α2Aγ2 and α2Gγ2 instead of nearly 100% α2Aγ2. In order to explain the unusual γ-chain ratio, sequencing of the Gγ promoter was carried out and revealed two nucleotide substitutions in cis: C→T at position -474 and A→G at position -309 from the Cap site. The latter had previously been observed in subjects with raised HbF levels, although it has not yet been evaluated at functional level. We used the luciferase assay to determine whether the two mutations modify the transcriptional activity of the Gγ promoter. Results indicated that the observed in vivo Gγ-globin production cannot be translated into increased in vitro promoter function, suggesting that the assessed mutations cannot be considered as functional single nucleotide polymorphisms per se; instead, a more complex regulatory mechanism might be involved.

High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.

Background: Dysregulated production of cytokines has a critical role in systemic lupus. The aim of this work is to identify, by a comprehensive analysis of IL-1 family cytokines and receptors in serum, correlation between cytokines/receptors' levels and the clinical and serological features of the disease.Methods: A full clinical evaluation was performed in 74 patients with systemic lupus erythematosus (SLE). C3, C4, anti-dsDNA and anti-C1q antibodies were measured. Cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein (IL-18BP)) were measured in serum by multiarray ELISA. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Data were analysed by non-parametric tests and by multivariate analysis, using partial least squares (PLS) models.Results: Total IL-18, IL-18BP, sIL-1R4 and IL-1Ra levels were higher in SLE vs. controls. Total and free IL-18 and sIL-1R4 were higher in patients with active vs. inactive disease and correlated with ECLAM, anti-C1q and anti-dsDNA antibodies. sIL-1R2 was higher in patients with inactive disease, was negatively correlated with ECLAM and anti-C1q antibodies and was positively correlated with C3 levels. PLS identified sIL-1R4, sIL-1R2 and anti-dsDNA as variables distinguishing patients with active from those with inactive disease; sIL-1R4, IL-18BP and anti-dsDNA identified patients with active nephritis; sIL-1R4, C3, IL-18 and free IL-18 identified patients with haematological involvement.Conclusion: The data support the use of IL-18, sIL-1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE.

Objectives Anti-citrullinated protein/peptide antibodies (ACPA) represent an important tool for the diagnosis of rheumatoid arthritis (RA) and the presence of multiple ACPA specificities is highly correlated with the evolution towards RA. However, little is known about the association of single specificities with disease manifestations and response to therapy in established RA. The aim of this work is to evaluate in a retrospective study the clinico-serological association of ACPA detected using VCP1 and VCP2 (EBV-derived citrullinated peptides) and HCP1 and HCP2 (histone-H4-derived citrulinated peptides) in established RA. Methods In 413 RA patients, anti-VCP1, -VCP2, -HCP1, -HCP2 were measured by ELISA. Patients were evaluated for systemic involvement, disease activity/severity, ongoing and past therapies. Data were analyzed by cluster analysis (CA) and principal component analysis (PCA). Results Anti-VCP1 were detected in 44% of RA patients; anti-VCP2 in 52%; anti-HCP1 in 46% and anti-HCP2 in 63%. CA and PCA independently demonstrated that ACPA levels are associated with RF positivity, and lung involvement. Subdividing patients in 5 groups according to the number of anti-peptide antibodies, mean antibody level and RF positivity, as well as the frequency of lung involvement, progressively increase in parallel with the number of ACPA specificities. Conclusions Higher number/levels of ACPA subtypes is associated with lung involvement but not with erosive disease. Moreover, a broader ACPA repertoire may identify patients treated with biological therapy, probably affected by a more severe disease. In conclusion, ACPA typing might be relevant for a better characterization of some disease features in established RA.

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.

Background Anti-citrullinated protein/peptide antibodies (ACPA) represent an important tool for the diagnosis of RA and the presence of multiple ACPA specificities is highly correlated with the evolution towards RA. 1 However, a limited amount of information is available on the predictive value of single specificities on disease manifestations and response to therapy in established RA The aim of the present work is to evaluate the diagnostic and prognostic value of the combined use of four well established citrullinated peptides as antigens for ACPA detection: VCP1 and VCP2 (derived from EBV proteins) and HCP1 and HCP2 (derived from histone H4). 2,3 Materials and methods Four hundred and forty-eight RA patients, followed in the Clinical Immunology Unit, University of Pisa, and in the Rheumatology Unit, University of Perugia, were recruited. RA patients were evaluated for systemic involvement, disease activity and severity, ongoing and past therapies. Anti-VCP1, -VCP2, -HCP1, -HCP2 were measured by home-made ELISA. Data were analysed by cluster analysis and principal component analysis. Results Antibodies to VCP1 were detected in 52% of RA patients; anti-VCP2 in 59,5%; anti-HCP1 in 57% and anti-HCP2 in 57,5% Cluster analysis and principal component analysis identify two subpopulations, that differ for ACPA levels, RF positivity, lung involvement and higher use of biological therapy. Patients were also subdivided in 5 groups according to the number of anti-peptide antibodies (negative for any, positive for one, for two, for three, for four). Mean antibody level and RF positivity progressively increased from the first to the last group, as well as the frequency of lung involvement. Conclusions ACPA are a family of antibodies with overlapping specificities. The results obtained with citrullinated peptides from EBV proteins and histone H4 suggest that fingerprinting of ACPA may be informative in established RA. A higher number of ACPA subtypes is predictive of lung involvement. Moreover, a broader ACPA repertoire also emerged as a feature of patients treated with biological therapy, thus probably affected by a more severe form of the disease. In conclusion, ACPA typing may be relevant for a better characterisation of some disease features in established RA. References 1. Brink M, Hansson M, Mathsson L, et al . Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum. 2013;65(4):899–910 2. Panza F, Pratesi F, Valoriani D, et al . Immunoglobulin G subclass profile of anticitrullinated peptide antibodies specific for Epstein Barr virus-derived and histone-derived citrullinated peptides. J Rheumatol2014;41(2): 407–8. 3. Johansson L, Pratesi F, Brink M, et al . Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis. Arthritis Res Ther2016;18(1):127.