Evidences for a Late Cretaceous continental arc in the Central Pontides: new insights on alternative geodynamic reconstructions for the Neotethys in Northern Turkey

The Intra-Pontide Suture Zone (IPSZ) is the less known one among the suture zones present in Turkey. The IPSZ is well exposed along the Daday-Arac-Kursunlu and Tosya – Emirköy geotraverses where several tectonic units can be recognized. Most of these units are characterized by the occurrence of basic rocks reflecting distinct tectonic origins and geochemical signatures. The study of the basic rocks emerges as an important tool for the geodynamic reconstruction as it can reveal the occurrence of of different types of oceanic basins, the development of a magmatic arc or the presence of rifting-related magmatism. The study of the geotraverses indicates that the imbricate stack of the IPSZ consists of four distinct tectonic units whose successions bear basic rocks: the Aylı Dağ ophiolite Unit, the Arkot Dağ Mèlange and two metamorphic units, referred to as Daday and Devrekani Units. This imbricate stack is probably the result of several episodes of out-of-sequence thrusts that affected the whole IPSZ. The Aylı Dağ Unit includes an about 5 km-thick ophiolite sequence topped by the middle Bathonian to early Callovian radiolarian cherts. In addition, a metamorphic sole is present at the base of the serpentinized peridotites. The geochemical evaluation of pillow-basalts and dykes highlights subduction-related characteristics, similar to IAT- and BABB-type lavas generated above intra-oceanic subduction systems. The Arkot Dağ Mèlange consists of an assemblage of slide-blocks, with different size and lithology, enclosed in a Late Santonian sedimentary matrix. The slide-blocks also include ophiolitic lithologies, mainly represented by basalts, but gabbros and peridotites are also found. The slide-blocks of basalts display affinites to IAT- and BABB-type magmas, signifying the involvement of subduction component, whereas no MORB-like basalt have been found. The Daday unit is characterized by metasedimentary and metabasic rocks deformed under blueschist to subgreenschist metamorphic facies conditions. The metasedimentary rocks include mica-bearing schists, fine-grained marbles and black quartzites. The metabasic lithologies, on the other hand, comprise actinolite-bearing schists and Naamphibole- bearing varieties possibly derived from basaltic and gabbroic protoliths. The metabasic rocks have a wide range of chemical compositions, displaying N-MORB-, E-MORB-, OIB- BABB- and IAT-type signatures. The Devrekani Unit is represented by an assemblage of amphibolites, marbles and micaschists showing a metamorphic climax developed under upper amphibolite facies in the Late Jurassic time. The amphibolites display EMORB-, OIB- BABB- and IAT-type signatures. The geochemical signature of the studied basic rocks provide the evidence that all the basic rocks from the tectonic units of IPSZ are derived by a supra-subduction zone. This finding can provide new nsights for the recostruction of the sgeodynamic history of the Intra-Pontide domain

PEGylation Promotes Hemoglobin Tetramer Dissociation

Hemoglobin conjugated with poly(ethylene glycol) (PEG) acts as an oxygen carrier free in plasma, substituting red blood cells in supplementing oxygen in hypo-oxygenation pathologies. Given the complexity of oxygen delivery controls, subtle structural and functional differences in PEGylated hemoglobins might be associated with distinct physiological responses and, potentially, adverse effects. We have compared hemoglobin PEGylated under anaerobic conditions, called PEG-Hb(deoxy), with hemoglobin PEGylated under aerobic conditions, called PEG-Hb(oxy), a product that mimics Hemospan, produced by Sangart, Inc. SDS PAGE and MALDI-TOF analyses demonstrated that PEG conjugation yields products characterized by a broad distribution of PEG/hemoglobin ratios. The elution profiles in size-exclusion chromatography indicate that both products exhibit a more homogeneous distribution of molecular weight/hydrodynamic volume under deoxy conditions and at higher concentrations. PEG-Hb(oxy) shows high oxygen affinity, low modulation of allosteric effectors, almost no cooperativity, a fast and monophasic CO binding, and a limited dependence of functional properties on concentration, whereas PEG-Hb(deoxy) exhibits oxygen binding curves that significantly depend on protein concentration, and a slow CO binding, similar to native hemoglobin. PEGylated CO-hemoglobins, probed by flash photolysis, exhibited a lower amplitude for the geminate rebinding phase with respect to native hemoglobin and a negligible T state bimolecular CO rebinding phase. These findings are explained by an increased dissociation of PEGylated hemoglobins into dimers and perturbed T and R states with decreased quaternary transition rates. These features are more pronounced for PEG-Hb(oxy) than PEG-Hb(deoxy). The detected heterogeneity might be a source of adverse effects when PEGylated Hbs are used as blood substitutes

Lung ultrasound: a new tool for the cardiologist

For many years the lung has been considered off-limits for ultrasound. However, it has been recently shown that lung ultrasound (LUS) may represent a useful tool for the evaluation of many pulmonary conditions in cardiovascular disease. The main application of LUS for the cardiologist is the assessment of B-lines. B-lines are reverberation artifacts, originating from water-thickened pulmonary interlobular septa. Multiple B-lines are present in pulmonary congestion, and may help in the detection, semiquantification and monitoring of extravascular lung water, in the differential diagnosis of dyspnea, and in the prognostic stratification of chronic heart failure and acute coronary syndromes

Nucleosynthesis Calculations for the Ejecta of Neutron Star Coalescences

We present the results of fully dynamical r-process network calculations for the ejecta of neutron star mergers (NSMs). The late stages of the inspiral and the final violent coalescence of a neutron star binary have been calculated in detail using a 3D hydrodynamics code (Newtonian gravity plus backreaction forces emerging from the emission of gravitational waves) and a realistic nuclear equation of state. The found trajectories for the ejecta serve as input for dynamical r-process calculations where all relevant nuclear reactions (including beta-decays depositing nuclear energy in the expanding material) are followed. We find that all the ejected material undergoes r-process. For an initial Ye close to 0.1 the abundance distributions reproduce very accurately the solar r-process pattern for nuclei with A above 130. For lighter nuclei strongly underabundant (as compared to solar) distributions are encountered. We show that this behaviour is consistent with the latest observations of very old, metal-poor stars, despite simplistic arguments that have recently been raised against the possibility of NSM as possible sources of Galactic r-process material.Comment: 5 pages, 2 figures, proceedings of Nuclei in the Cosmos 2000, to be published in Nucl. Phys. A; minor correctio

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study.

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0-2.0 mg/kg/day) among adults and 2-4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors

Orbital/ocular inflammatory involvement in VEXAS syndrome: Data from the international AIDA network VEXAS registry

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03–5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up

Development and Implementation of the AIDA International Registry for Patients with Non-Infectious Uveitis

Introduction: The aim of this paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry for paediatric and adult patients with non-infectious uveitis (NIU). Methods: This is a physician-driven, population- and electronic-based registry implemented for both retrospective and prospective collection of real-world demographics, clinical, laboratory, instrumental and socioeconomic data of patients with uveitis and other non-infectious inflammatory ocular diseases recruited through the AIDA Network. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is thought to collect standardised information for real-life research and has been developed to change over time according to future scientific acquisitions and potentially communicate with other similar instruments. Security, data quality and data governance are cornerstones of this platform. Results: Ninety-five centres have been involved from 19 countries and four continents from 24&nbsp;March to 16&nbsp;November 2021. Forty-eight out of 95 have already obtained the approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers). The AIDA Registry collects baseline and follow-up data using 3943 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger/risk factors, therapies and healthcare utilization for patients with NIU. Conclusions: The development of the AIDA Registry for patients with NIU will facilitate the collection of standardised data leading to real-world evidence and enabling international multicentre collaborative research through inclusion of patients and their families worldwide

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis syndrome

Objective: Aim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Methods: This is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries. Results: A total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems. Conclusions: The development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on NCT 05200715