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In the context of the Gamma-Flash program, whose objective is to investigate the emission of high-energy gamma rays and neutrons during thunderstorms, a neutron detection system, based on scintillators coupled to photomultiplier tubes (PMTs), has been developed. The neutrons emitted are generated by photoproduction reactions in the atmosphere, and they have a wide range of energies, from MeV down to meV. In this work, the effects of neutron irradiation on PMTs and their power supply are investigated to assess and quantify the effects of irradiation on dark-count rate and during data acquisition. The detection system was irradiated at the ChipIr beamline at ISIS Neutron and Muon Source, Didcot, U.K. During the irradiation of power supplies, an increase in dark-count rate has been observed, whose magnitude depends on the output voltages and the experimental parameters. In the specific case of our experiment, the dark-count rate went from an average value of 0 to 40 and 120 counts per second (counts/s) at the operating voltage of 1800 and 1900 V, respectively. Even more evident are the effects during the irradiation of the PMTs; in this case, the dark-count rate reaches about 4000 counts/s, high enough to hamper the measurements. These effects, despite their relevance to data acquisition and detector performance, do not produce long-term consequences on the electronic components. Beyond the Gamma-Flash program, this research is relevant, because the use of PMTs is common in many areas of scientific research and radiation detection applications. Our results highlight the need for great care in the interpretation of results in applications where PMTs and their power supplies may be exposed to high radiation fluxes. A proper design of the experiment or shielding strategies could prevent such unwanted behavior in data acquisition.

Background: A difficulty score for laparoscopic adrenalectomy (LA) is lacking in the literature. A retrospective cohort study was designed to develop a preoperative “difficulty score” for LA. Methods: A multicenter study was conducted involving four Italian tertiary centers for adrenal disease. The population was randomly divided into two subsets: training group and validation one. A multicenter study was undertaken, including 964 patients. Patient, adrenal lesion, surgeon’s characteristics, and the type of procedure were studied as potential predictors of target events. The operative time (pOT), conversion rate (cLA), or both were used as indicators of the difficulty in three multivariate models. All models were developed in a training cohort (70% of the sample) and validated using 30% of patients. For all models, the ability to predict complicated postoperative course was reported describing the area under the curve (AUCs). Logistic regression, reporting odds ratio (OR) with p-value, was used. Results: In model A, gender (OR 2.04, p= 0.001), BMI (OR 1.07, p= 0.002), previous surgery (OR 1.29, p= 0.048), site (OR 21.8, p< 0.001) and size of the lesion (OR 1.16, p= 0.002), cumulative sum of procedures (OR 0.99, p< 0.001), extended (OR 26.72, p< 0.001) or associated procedures (OR 4.32, p= 0.015) increased the pOT. In model B, ASA (OR 2.86, p= 0.001), lesion size (OR 1.20, p= 0.005), and extended resection (OR 8.85, p= 0.007) increased the cLA risk. Model C had similar results to model A. All scores obtained predicted the target events in validation cohort (OR 1.99, p< 0.001; OR 1.37, p= 0.007; OR 1.70, p< 0.001, score A, B, and C, respectively). The AUCs in predicting complications were 0.740, 0.686, and 0.763 for model A, B, and C, respectively. Conclusion: A difficulty score based on both pOT and cLA (Model C) was developed using 70% of the sample. The score was validated using a second cohort. Finally, the score was tested, and its results are able to predict a complicated postoperative course.

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Environmental variables may markedly influence egg parasitoid performance and must be considered when choosing the best release strategy. Thus, this study aimed to investigate the effects of light, temperature, soil moisture, and precipitation on the emergence and parasitism of parasitoid releases of unprotected and encapsulated pupae. The presence of light favored the parasitism of Trichogramma pretiosumRiley, 1879, and Telenomus remus(Nixon, 1937) but did not impact the parasitism of Telenomus podisi(Ashmead, 1893). The release strategy adopted (release of encapsulated or unprotected pupae) also impacted the results. On one hand, card capsules gave protection against rainfall, limited to 10 mm regarding Tr. pretiosum, while on the other hand, card capsules led to a reduction in the number of captured adults for Te. podisiat 25°C and 30°C. Therefore, Tr. pretiosum, Te. remus, and Te. podisican be released using both encapsulated and unprotected pupae, with advantages and disadvantages for each strategy, depending on each studied environmental variable. In addition, parasitoid pupae should be released so that the majority emerge during daylight, especially for Te. remusand Tr. pretiosum, since parasitism was greatly reduced in dark environments. Telenomus podisiis not affected by this variable as it demonstrated similar parasitism in light and dark environments.

Combined antiretroviral therapy (cART) for HIV-1 dramatically slows disease progression among HIV+individuals. Currently, lymphoma represents the main cause of death among HIV-1-infected patients. Detection of p17 variants (vp17s) endowed with B-cell clonogenic activity in HIV-1-seropositive patients with lymphoma suggests their possible role in lymphomagenesis. Here, we demonstrate that the clonogenic activity of vp17s is mediated by their binding to PAR1 and to PAR1-mediated EGFR transactivation through Gq protein. The entire vp17s-triggered clonogenic process is MMPs dependent. Moreover, phosphoproteomic and bioinformatic analysis highlighted the crucial role of EGFR/PI3K/Akt pathway in modulating several molecules promoting cancer progression, including RAC1, ABL1, p53, CDK1, NPM, Rb, PTP-1B, and STAT1. Finally, we show that a peptide (F1) corresponding to the vp17s functional epitope is sufficient to trigger the PAR1/EGFR/PI3K/Akt pathway and bind PAR1. Our findings suggest novel potential therapeutic targets to counteract vp17-driven lymphomagenesis in HIV+patients.

Infective endocarditis (IE) is a life-threatening disease, mostly caused by gram-positive cocci, needing a 4–6 weeks antibiotic course. Dalbavancin is a lipoglycopeptide active on gram-positive microorganisms, with a unique pharmacokinetic profile. We describe our experience with dalbavancin to complete the intravenous antibiotic regimen for difficult-to-treat IE cases due to gram-positive bacteria. We treated 10 severely ill patients, each presenting several comorbidities. Seven patients were microbiologically cured from IE, but two patients experienced IE relapse due to the same microrganism. Short-term mortality after dalbavancin was nil, but late mortality (within 1 year of hospital discharge) was 60%. No death was related to dalbavancin therapy. Treatment was generally well tolerated. Dalbavancin may be an option to complete IE treatment in selected cases, once blood culture clearance and improvement of clinical conditions under standard therapy is reached, allowing shortening of hospitalization.

Psoriasis is an inflammatory disease of the epidermis based on an immunological mechanism involving Langerhans cells and T lymphocytes that produce pro-inflammatory cytokines. Genetic factors, environmental factors, and improper nutrition are considered triggers of the disease. Numerous studies have reported that in a high number of patients, psoriasis is associated with obesity. Excess adipose tissue, typical of obesity, causes a systemic inflammatory status coming from the inflammatory active adipose tissue; therefore, weight reduction is a strategy to fight this pro-inflammatory state. This study aimed to evaluate how a nutritional regimen based on a ketogenic diet influenced the clinical parameters, metabolic profile, and inflammatory state of psoriasis patients. To this end, 30 psoriasis patients were subjected to a ketogenic nutritional regimen and monitored for 4 weeks by evaluating the clinical data, biochemical and clinical parameters, NMR metabolomic profile, and IL-2, IL-1β, TNF-α, IFN-γ, and IL-4 concentrations before and after the nutritional regimen. Our data show that a low-calorie ketogenic diet can be considered a successful strategy and therapeutic option to gain an improvement in psoriasis-related dysmetabolism, with significant correction of the full metabolic and inflammatory status.

d-Amino acids were believed to occur only in bacteria and invertebrates. Today, it is well known that d-amino acids are also present in mammalian tissues in a considerable amount. In particular, high levels of free d-serine (d-Ser) and d-aspartate (d-Asp) are found in the brain. While the functions of d-Ser are well known, many questions remain unanswered regarding the role of d-Asp in the central nervous system. d-Asp is very abundant at the embryonic stage, while it strongly decreases after birth because of the expression of d-aspartate oxidase (Ddo) enzyme, which catalyzes the oxidation of this d-amino acid into oxaloacetate, ammonium, and hydrogen peroxide. Pharmacologically, d-Asp acts as an endogenous agonist of N-methyl d-aspartate and mGlu5 receptors, which are known to control fundamental brain processes, including brain development, synaptic plasticity, and cognition. In this work, we studied a recently generated knockin mouse model (R26ddo/ddo), which was designed to express DDO beginning at the zygotic stage. This strategy enables d-Asp to be almost eliminated in both prenatal and postnatal lives. To understand which biochemical pathways are affected by depletion of d-Asp, in this study, we carried out a metabolomic and lipidomic study of ddoknockin brains at different stages of embryonic and postnatal development, combining nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) techniques. Our study shows that d-Asp deficiency in the brain influences amino acid pathways such as threonine, glycine, alanine, valine, and glutamate. Interestingly, d-Asp is also correlated with metabolites involved in brain development and functions such as choline, creatine, phosphocholine (PCho), glycerophosphocholine (GPCho), sphingolipids, and glycerophospholipids, as well as metabolites involved in brain energy metabolism, such as GPCho, glucose, and lactate.

Angiogenesis, the formation of new blood vessels from preexisting ones, is crucial for tumor growth and metastatization, and is considered a promising therapeutic target. Unfortunately, drugs directed against a specific proangiogenic growth factor or receptor turned out to be of limited benefit for oncology patients, likely due to the high biochemical redundancy of the neovascularization process. In this scenario, multitarget compounds that are able to simultaneously tackle different proangiogenic pathways are eagerly awaited. UniPR1331 is a 3β-hydroxy-Δ5-cholenic acid derivative, which is already known to inhibit Eph–ephrin interaction. Here, we employed an analysis pipeline consisting of molecular modeling and simulation, surface plasmon resonance spectrometry, biochemical assays, and endothelial cell models to demonstrate that UniPR1331 directly interacts with the vascular endothelial growth factor receptor 2 (VEGFR2) too. The binding of UniPR1331 to VEGFR2 prevents its interaction with the natural ligand vascular endothelial growth factor and subsequent autophosphorylation, signal transduction, and in vitro proangiogenic activation of endothelial cells. In vivo, UniPR1331 inhibits tumor cell-driven angiogenesis in zebrafish. Taken together, these data shed light on the pleiotropic pharmacological effect of UniPR1331, and point to Δ5-cholenic acid as a promising molecular scaffold for the development of multitarget antiangiogenic compounds.

Aim:The present study aims at investigating the possible correlation between peripheral markers of inflammation and brain networks.Introduction:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease dominated by progressive motor impairment. Among the complex mechanisms contributing to the pathogenesis of the disease, neuroinflammation, which is associated with altered circulating cytokine levels, is suggested to play a prominent role.Methods:Based on magnetoencephalography data, we estimated topological properties of the brain networks in ALS patients and healthy controls. Subsequently, the blood levels of a subset of cytokines were assayed. Finally, we modeled the brain topological features in the function of the cytokine levels.Results:Significant differences were found in the levels of the cytokines interleukin (IL)-4, IL-1β, and interferon-gamma (IFN-γ) between patients and controls. In particular, IL-4 and IL-1β levels increased in ALS patients, while the IFN-γ level was higher in healthy controls. We also detected modifications in brain global topological parameters in terms of hyperconnectedness. Despite both blood cytokines and brain topology being altered in ALS patients, such changes do not appear to be in a direct relationship.Conclusion:Our results would be in line with the idea that topological changes relate to neurodegenerative processes. However, the absence of correlation between blood cytokines and topological parameters of brain networks does not preclude that inflammatory processes contribute to the alterations of the brain networks.Impact statementThe progression of amyotrophic lateral sclerosis entails both neurodegenerative and inflammatory processes. Furthermore, disease progression induces global modifications of the brain networks, with advanced stages showing a more compact, hyperconnected network topology. The pathophysiological processes underlying topological changes are unknown. In this article, we hypothesized that the global inflammatory profile would relate to the topological alterations. Our results showed that this is not the case, as modeling the topological properties as a function of the inflammatory state did not yield good predictions. Hence, our results suggest that topological changes might directly relate to neurodegenerative processes instead.

•Data on the use of ceftobiprole in severely ill patients, are limited.•A favourable clinical outcome was observed in 20 of 29 patients receiving ceftobiprole.•Three patients had ceftobiprole-related toxicity, including two cases of myoclonus.•No major adverse effect on bone marrow, kidney or liver function was observed.•Ceftobiprole is a safe and effective treatment for bacterial infections.

Background: The aim is to evaluate safety and efficacy of near infra-red (NIR) indocyanine green (ICG) fluorescence structural imaging during laparoscopic cholecystectomy (LC) (Group A) and to compare perioperative data, including operative time, with a series of patients who underwent LC with routine traditional intraoperative cholangiography (IOC) (Group B). Methods: Forty-four patients with acute or chronic cholecystitis underwent NIR-ICG fluorescent cholangiography during LC. ICG was administered intravenously at different time intervals or by direct gallbladder injection during surgery. Fluorescence intensity and anatomy identification were scored according to a visual analogue scale between 1 (least accurate) and 5 (most accurate). Group B patients (n= 44) were chosen from a prospectively maintained database of patients who underwent LC with routine IOC, matched for age, sex, body mass index, and diagnosis with group A patients. Results: No adverse reactions were recorded. In group A, mean time between intravenous administration of ICG and surgery was 10.7 ± 8.2 (range 2–52) h. Administered doses ranged from 3.5 to 13.5 mg. Fluorescence was present in all cases, scoring ≥ 3 in 41 patients. Mean operative time was 86.9 ± 36.9 (30–180) min in group A and 117.9 ± 43.4 (40–220) min in group B (p= 0.0006). No conversion to open surgery nor bile duct injuries were observed in either group. Conclusions: LC with NIR-ICG fluorescent cholangiography is safe and effective for early recognition of anatomical landmarks, reducing operative time as compared to LC with IOC, even when residents were the main operator. NIR-ICG fluorescent cholangiography was effective in patients with acute cholecystitis and in the obese. Data collection into large registries on the results of NIR-ICG fluorescent cholangiography during LC should be encouraged to establish whether this technique might set a new safety standard for LC.

Up to now, only few works focused on the meteorological context leading to the production of Terrestrial Gamma ray Flashes (TGFs). In this study, we carry out, for the first time, an analysis on large scale of the meteorological scenario linked to 278 TGFs detected by RHESSI, AGILE, and Fermi, by using the Meteosat Second Generation geostationary satellites. These satellites are useful as they continuously monitor the same geographic region in time, allowing investigations on thunderstorms' development; moreover, they are endowed with channels and products that provide information about the meteorological context under analysis, such as the cloud top temperature and altitude, the cloud extension, the drop effective radius and the cloud phase. Our work confirms what previously found in other studies about the TGF‐associated thunderstorms, by using a different approach and by using for the first time the Meteosat satellites: we find TGFs mostly linked to the development phase of deep convective thunderstorm systems, exhibiting typical characteristics of tropical storms, and providing a first picture on large scale of the TGF‐associated thunderstorm systems. Thunderstorms associated to TGF production mainly occur at low latitudes, over land regions, and in the afternoonMost of the thunderstorms found producing TGFs exhibit a wide range of cloud top temperatures and cloud extensions, but high cloud top heightsTGFs tend to occur within ±5 min from the peak lightning activity of the associated thunderstorm

The new on-board AGILE MiniCalorimeter -Gravitational Waves(MCAL-GW) configuration increased the detector trigger capabilities for short duration high-energy transients, such as short duration sub-threshold events (STEs), as well as short gamma-ray bursts (GRBs). The aim of this change was the improvement of the satellite trigger logic, to make AGILE more competitive in the detection of possible electromagnetic counterparts to gravitational waves detected by the LIGO/Virgo experiments. At the moment, a new pipeline system has been established, running an automatic search algorithm, aimed at processing the MCAL data, searching for GRB and STE signatures, promptly distributing data to the AGILE Team, for more advanced offline analysis. The new MCAL-GW configuration substantially improved the detection capabilities of MCAL, leading to the detection of 52 GRBs and more than 2 × 104STEs.

AGILE is a space mission of the Italian Space Agency dedicated to X-ray and gamma-ray astrophysics operating since 2007. Since the discovery of gravitational wave (GW) events by the LIGO-Virgo Collaboration (LVC) announced in February 2016, AGILE is playing a very important role in the search for possible X-ray and gamma-ray counterparts. The large fields of view of the gamma-ray and hard X-ray imagers (2.5 sr and 1 sr, respectively) and the current spinning mode allow AGILE to cover at any moment a very large fraction of the sky. We present here an overview of AGILE observations of GW events during the LVC observing periods O1 and O2 which span the time interval September 2015–August 2017. In particular, we focus on the main characteristics of AGILE observations of the events GW150914, GW170104, and GW170817. The latter event is of great relevance being associated with a “kilonova” counterpart: we establish important physical constraints on the possible γ-ray emission from a magnetar-like remnant in the first ∼1000s following the GW event time. We also present further developments and preliminary results obtained in preparation of the O3 observing run (start in April 2019). AGILE is fully operative in the search for GW event counterparts, and continues to observe the sky in a unique way because of its combination of large field-of-view hard X-ray and gamma-ray detectors.

Despite the recognition from their discovery that terrestrial gamma ray flashes (TGFs) originate from thunderstorms, little is known about the TGF-producing storms. The characteristics of such thunderstorms are investigated here using meteorological data, with the aim to set up a framework of analysis to be propagated to more complete TGF archives. In this work, we present the preliminary results. As first analysis, we considered 72 events detected by the Astrorivelatore Gamma ad Immagini Leggero (AGILE) from March 2015 to June 2015, estimating their electric activity in terms of flash production. To this end, we examined World Wide Lightning Location Network lightning data in the spatial and temporal proximity of each AGILE TGFs, searching for relationship between flash rate peak and distribution and the TGF occurrence. Moreover, we analyzed the low-Earth orbiting (LEO) satellite observation of the TGF-producing storms to define, through the capabilities of microwave sensors (both active and passive), the structure of the convective storms correlated with TGF events. In particular, we focused on the Global Precipitation Measurement (GPM) observations and show here a case study observed by the dual-frequency precipitation radar (DPR). Preliminary results indicate that the TGF often occur during the most active lightning phase of the storm, while the intensity of the storm is not a key ingredient for the production of a TGF. The multisensory capability of LEO satellites provide a picture of the storm structure, that, despite the poor coverage, is an unprecedented tool to study such cloud system over remote areas and open ocean. This study framework is meant to be applied to other TGF database, such as the ones collected by other space missions (e.g., FERMI, RHESSI).

AGILE is one of the satellites currently detecting terrestrial gamma-ray flashes (TGFs). In particular, the AGILE MiniCALorimeter detected more than 2000 events in 8 years activity, by exploiting a unique sub-millisecond timescale trigger logic and high-energy range. A change in the onboard configuration enhanced the trigger capabilities for the detection of these events, overcoming dead time issues and enlarging the detection rate of these events up to >50TGFs/month, allowing to reveal shorter duration flashes. The quasi-equatorial low-inclination (2.5∘) orbit of AGILE allows for the detection of repeated TGFs coming from the same storms, at the same orbital passage and throughout successive orbital overpasses, over the same geographic region. All TGFs detected by AGILE are fulfilling a database that can be used for offline analysis and forthcoming studies. The limited number of missions currently detecting these brief terrestrial flashes makes the understanding of this phenomenon very challenging and, in this perspective, the AGILE satellite played and still plays a major role, helping shedding light to many aspects of TGF science.

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1–6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7–9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10−6to 1012electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.

Background: The aim of this study is to evaluate the feasibility, safety, advantages and surgical outcomes of laparoscopic bilateral adrenalectomy (LBA) by an anterior transperitoneal approach. Methods: From 1994 to 2018, 552 patients underwent laparoscopic adrenalectomy, unilateral in 531 and bilateral in 21 patients (9 females and 12 males). All patients who underwent LBA were approached via a transperitoneal anterior route and form our study population. Indications included: Cushing’s disease (n?=?11), pheochromocytoma (n?=?6), Conn’s disease (n?=?3) and adrenal cysts (n?=?1). Results: Mean operative time was 195?±?86.2 min (range 55–360 min). Conversion was necessary in one case for bleeding. Three patients underwent concurrent laparoscopic cholecystectomy with laparoscopic common bile duct exploration and ductal stone extraction in one. Three postoperative complications occurred in one patient each: subhepatic fluid collection, intestinal ileus and pleural effusion. Mean hospital stay was 6.1?±?4.7 days (range 2–18 days). Conclusions: In our experience, transperitoneal anterior LBA was feasible and safe. Based on our results, we believe that this approach leads to prompt recognition of anatomical landmarks with early division of the main adrenal vein prior to any gland manipulation, with a low risk of bleeding and without the need to change patient position. Unlike the lateral approach, there is no need to mobilize the spleno-pancreatic complex on the left or the liver on the right. The ability to perform associated intraperitoneal procedures, if required, is an added benefit.

Introduction:CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) who have received one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. CARTITUDE-4 demonstrated superiority of cilta-cel over PVd and DPd on progression-free survival (PFS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or stringent CR]). Other available therapies for the treatment of this patient population where individual patient data was available for analysis include: daratumumab in combination with bortezomib and dexamethasone (DVd), bortezomib in combination with dexamethasone (Vd), carfilzomib in combination with daratumumab and dexamethasone (DKd) or dexamethasone alone (Kd), and pomalidomide in combination with dexamethasone (Pd). This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm (i.e., patients apheresed or infused with cilta-cel) in CARTITUDE-4 vs each of these regimens in the same target population.

Terrestrial gamma ray flashes (TGFs) are very short bursts of gamma radiation associated to thunderstorm activity and are the manifestation of the highest‐energy natural particle acceleration phenomena occurring on Earth. Photon energies up to several tens of megaelectronvolts are expected, but the actual upper limit and high‐energy spectral shape are still open questions. Results published in 2011 by the AGILE team proposed a high‐energy component in TGF spectra extended up to ≈100 MeV, which is difficult to reconcile with the predictions from the Relativistic Runaway Electron Avalanche (RREA) mechanism at the basis of many TGF production models. Here we present a new set of TGFs detected by the AGILE satellite and associated to lightning measurements capable to solve this controversy. Detailed end‐to‐end Monte Carlo simulations and an improved understanding of the instrument performance under high‐flux conditions show that it is possible to explain the observed high‐energy counts by a standard RREA spectrum at the source, provided that the TGF is sufficiently bright and short. We investigate the possibility that single high‐energy counts may be the signature of a fine‐pulsed time structure of TGFs on time scales ≈4 μs, but we find no clear evidence for this. The presented data set and modeling results allow also for explaining the observed TGF distribution in the (Fluence × duration) parameter space and suggest that the AGILE TGF detection rate can almost be doubled. TGFs detected by AGILE with counts energy larger than 40 MeV are compatible with RREAData show no evidence of a fine time structure of TGFs on microsecond time scale.TGFs simultaneous to lightning suggest that the AGILE TGF sample can be significantly increased

AGILE is a space mission launched in 2007 to study X-ray and gamma-ray phenomena through data acquired by different instruments on board the satellite. In the multi-messenger era, the fast detection of transient sources is one of the main goals of space and ground-based gamma-ray observatories. When an observatory detects a transient event, it usually sends science alerts to other facilities through networks such as the General Coordinates Network (GCN), enabling follow-up observations. To achieve this task, real-time analysis (RTA) pipelines are required. This manuscript presents the RTA system developed for the AGILE space mission to detect transient sources on timescales from seconds to one hour. Two types of pipelines are presented. One pipeline executes automated analyses as soon as data are available, sharing the detection of sources with the community; more than 90 automated notices have been sent to the GCN since May 2019. The other pipeline reacts to external science alerts from neutrinos, gravitational waves (GW), etc., to search for electromagnetic counterparts in the AGILE data. The AGILE Team can visualize the results of these analyses using a web platform. The pipelines hereby presented can be a starting point for the development of RTA systems of the next generation of space-based gamma-ray observatories.

ABSTRACTThe identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silicoprotein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42variants in MLID development and confirmed NLRP2as causative locus in BWS-MLID.

e-ASTROGAM (‘enhanced ASTROGAM’) is a breakthrough Observatory space mission, with a detector composed by a Silicon tracker, a calorimeter, and an anticoincidence system, dedicated to the study of the non-thermal Universe in the photon energy range from 0.3 MeV to 3 GeV – the lower energy limit can be pushed to energies as low as 150 keV for the tracker, and to 30 keV for calorimetric detection. The mission is based on an advanced space-proven detector technology, with unprecedented sensitivity, angular and energy resolution, combined with polarimetric capability. Thanks to its performance in the MeV–GeV domain, substantially improving its predecessors, e-ASTROGAM will open a new window on the non-thermal Universe, making pioneering observations of the most powerful Galactic and extragalactic sources, elucidating the nature of their relativistic outflows and their effects on the surroundings. With a line sensitivity in the MeV energy range one to two orders of magnitude better than previous generation instruments, e-ASTROGAM will determine the origin of key isotopes fundamental for the understanding of supernova explosion and the chemical evolution of our Galaxy. The mission will provide unique data of significant interest to a broad astronomical community, complementary to powerful observatories such as LIGO-Virgo-GEO600-KAGRA, SKA, ALMA, E-ELT, TMT, LSST, JWST, Athena, CTA, IceCube, KM3NeT, and LISA.

Systemic conditions can influence orthodontic tooth movement. This study evaluates histologic periodontal responses to orthodontic tooth movement in diabetes‐induced rats with or without periodontal disease. Forty Wistar rats were divided according their systemic condition (SC) into diabetic (D) and non‐diabetic (ND) groups. Each group was subdivided into control (C), orthodontic tooth movement (OM), ligature‐induced periodontitis (P) and ligature‐induced periodontitis with orthodontic movement (P+OM) groups. Diabetes mellitus (DM) was induced with alloxan monohydrate, and after 30 days, the P group received a cotton ligature around their first lower molar crown. An orthodontic device was placed in OM and P+OM groups for 7 days, and the animals were then euthanized. Differences in OM between D and ND groups were not significant (6.87± 3.55 mm and 6.81 ± 3.28 mm, respectively), but intragroup analysis revealed statistically significant differences between the P+OM groups for both SCs. Bone loss was greater in the D group (0.16 ± 0.07 mm2) than in the ND group (0.10 ± 0.03 mm2). In intragroup analysis of the D condition, the P+OM group differed statistically from the other groups, while in the ND condition, the P+OM group was different from the C and OM groups. There was a statistically significant difference in bone density between D and ND conditions (18.03 ± 8.09% and 22.53 ± 7.72%) in the C, P, and P+OM groups. DM has deleterious effects on bone density and bone loss in the furcation region. These effects are maximized when associated with ligature‐induced periodontitis with orthodontic movement.

Zusammenfassung.Der Begriff personenzentrierte Gesundheitsversorgung ist in aller Munde. Man könnte vermuten, dass es sich dabei um ein modisches Schlagwort handelt. Tatsächlich bezeichnet der Begriff ein theoretisch fundiertes Wertesystem, das weltweit zunehmend Beachtung findet.

An Airbus A340 aircraft flew over Northern Australia with the In‐Flight Lightning Damage Assessment System (ILDAS) installed onboard. A long‐duration gamma ray emission was detected. The most intense emission was observed at 12 km altitude and lasted for 20 s. Its intensity was 20 times the background counts, and it was abruptly terminated by a distant lightning flash. In this work we reconstruct the aircraft path and event timeline. The glow‐terminating flash triggered a discharge from the aircraft wing that was recorded by a video camera operating onboard. Another count rate increase was observed 6 min later and lasted for 30 s. The lightning activity as reported by ground networks in this region was analyzed. The measured spectra characteristics of the emission were estimated. Two gamma ray glows were observed at 12 km altitude over Northern AustraliaThe observation was conducted by the In‐flight Lightning Damage Assessment System (ILDAS)Gamma ray glow was terminated by a distant lightning flash

Oral anticoagulant therapy, such as vitamin K antagonists (VKAs), is prominent for the prevention of cerebral ischemic stroke or systemic embolism and all-cause mortality in patients with atrial fibrillation, venous thromboembolism, and mechanical or biological valve. VKA treatment requires monitoring of the international normalized ratio (INR) in order to maintain it in a therapeutic range, avoiding side effects, the main and most significant of which is bleeding. The aim of the present study was to evaluate the event rates of several clinical composite outcomes, such as bleeding, thromboembolic events, and all-cause death. We compared three organizational models distinguished by a total (from 1 January to 31 December 2015 in which PT/INR analysis with the relative internal and external quality controls was performed by the surveillance center) or partial (from 15 January to 15 July 2016 and from 15 August to 15 November 2016, in which the surveillance center had the ability to view only the PT/INR results or all patients analyses, including blood count, creatinine, liver enzymes, etc., respectively) analytical patient management. The present longitudinal follow-up study included 1225 patients, recruited from 1 January 2015 to 15 November 2016 at a surveillance center for the prevention of cerebral ischemic stroke and systemic embolism in Chieti (Italy). The results show a significant rise of the incidence rate ratio in patients undergoing VKA treatment during the period 15 January to 15 July 2016 compared to the previous one regarding total bleeding, especially for minor bleeding and digestive bleeding; thromboembolic events; and all-death cause. These findings show that analytical and clinical data and information should be under the direct supervision and responsibility of the surveillance center. In fact, this approach seems to highlight the best results in terms of safety and therapeutic effectiveness.

To investigate the effect of a quality improvement project that resulted in an infection control bundle to reduce the number of spinal cord stimulator (SCS) infections. The study was performed in a single center for neuromodulation from January 1, 2014, through May 31, 2016. In response to a high number of surgical site infections (SSIs) after SCS surgery, a multidisciplinary team analyzed the surgical process and developed an infection prevention bundle consisting of five items: 1) showering and decolonization for five days prior to surgery and showering in the hospital on the morning of surgery; 2) performing the SCS implantation as the first in the daily operating room (OR) program; 3) maintaining a minimal number of people in the OR; 4) providing home care nurses with a folder with SCS wound care instructions including pictures; 5) giving oral specific wound care instructions to patients. The number of infections was calculated for the baseline, implementation, and sustainability phases. A total of 410 SCS surgeries were performed during the study period. In the preintervention phase, 26/249 (10.4%) SCS surgeries were infected. During the implementation and sustainability phase, 2/59 (3.4%) and 1/102 (1.0%) SCS surgeries were infected, respectively. The reduction in the number of infections in pre and postintervention phase was statistically significant (p= 0.003). Multidisciplinary measures to reduce SSIs reduced the number of SCS associated infections in our study setting.

Terrestrial gamma ray flashes (TGFs) are brief (approximately hundreds of microseconds) intense gamma ray emissions coming from Earth's atmosphere (∼15 km above sea level), correlated with thunderstorms and atmospheric electric activity. Since their unexpected discovery in the early 1990s by the Burst And Transient Source Experiment/Compton Gamma Ray Observatory, TGFs have been further investigated by several satellites devoted to high‐energy astrophysics. The Astrorivelatore Gamma ad Immagini LEggero (AGILE) mission turned out to be particularly suitable to detect these events, due to a very wide energy range (up to 100 MeV), an optimized triggering system, and a unique low‐inclination near‐equatorial orbit (2.5°). We describe a detection system, developed for the AGILE satellite, whose aim is to provide real‐time meteorological information on each detected TGF. We take advantage of data acquired by geostationary satellites to promptly identify the associated storm and follow its evolution in space and time, in order to study its previous onset and development. Data from Low‐Earth Orbit meteorological satellites, such as the Global Precipitation Mission, as well as ground measurements from lightning detection networks, can be integrated in the pipeline. This system allows us a prompt characterization of the ground meteorological conditions at TGF time which will provide instrument‐independent trigger validation, fill in a database for subsequent statistical analysis, and eventually, on a longer term perspective, serve as a real‐time alert service open to the community. The AGILE satellite has a TGF database linked to meteorological informationGeostationary satellite data are processed to extract information on TGF‐producing thunderstormsThis pipeline allows for further meteorological studies about the physics of TGFs

Since their discovery, Terrestrial Gamma ray Flashes (TGFs) exhibited an evident correlation with thunderstorms and lightning activity. The fleeting nature of these events and the heavy absorption of gamma rays in the lowest atmospheric layers severely hamper the observation of this phenomenon, making us reveal just a small fraction of a probably much wider population. As each thunderstorm produces a large amount of lightning discharges during its lifetime, it is reasonable that even a large amount of TGFs are produced during the same event. However, detection of multiple TGFs coming from the same storm is difficult to perform, as it requires the constant monitoring of a spatially limited geographic region: this is not an easy task to perform for satellites on high‐inclination orbits that make them experience nonnegligible latitudinal shifts at each orbital passage over a certain region, preventing the monitoring of a limited geographic region throughout successive overpasses. In this perspective, the quasi‐equatorial (2.5°) orbit of the Astrorivelatore Gamma ad Immagini LEggero (AGILE) satellite ensures a minimal latitudinal shift when flying over the same region at successive passages, allowing for the follow‐up of thunderstorms in time. We exploit this feature of the AGILE satellite to search for multiple TGFs coming from the same geographic region and, in particular, from the same thunderstorm. We carry out this search on the AGILE TGF database (2009–2016), ending up with a sample of 79 systems producing more than one TGF, both during the same overpass and up to four overpasses after. Data acquired by geostationary meteorological satellites and cross correlation with radio sferics detected by World Wide Lightning Location Network are used to support this investigation. The AGILE satellite for the first time clearly establishes the multiple occurrences of TGFs from convective thunderstorms, both on timescales of minutes to several hours. The AGILE satellite observed more TGFs originating from the same spatially limited geographic regionsThis work represents an indirect evidence that more TGFs can be produced by thunderstorms throughout their lifetimeThe orbit of the AGILE satellite is unique to perform follow‐up of thunderstorms in time

Alzheimer′s disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D‐MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in‐house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors.

In selected patients with N0 rectal cancer, endoluminal loco-regional resection (ELRR) by transanal endoscopic microsurgery (TEM) may be an alternative treatment option to laparoscopic total mesorectal excision (LTME). Aim of this study is to evaluate the short- and medium-term quality of life (QoL) from a retrospective analysis of prospectively collected data in patients with iT2–iT3 N0-N+ rectal cancer, who underwent ELRR by TEM or LTME after neoadjuvant radio-chemotherapy (n-RCT). Thirty patients with iT2–iT3 rectal cancer who underwent ELRR by TEM (n= 15) or LTME (n= 15) were enrolled in this study. The choice for one operation or the other was made on the basis of predefined criteria. QoL was evaluated by EORTC QLQ-C30 and QLQ-CR38 questionnaires at admission, after n-RCT and 1, 6, and 12 months after surgery. No statistically significant differences in QoL evaluation were observed between the two groups, both at admission and after n-RCT. At 1 month after surgery, significantly better results in the ELRR group were observed by QLQ-C30 in: Nausea/Vomiting (p= 0.05), Appetite Loss (p= 0.003), Constipation (p= 0.05), and by QLQ-CR38 in: Body Image (p= 0.05), Sexual Functioning (p= 0.03), Future Perspective (p= 0.05) and Weight Loss (p= 0.036). At 6 months after surgery, a statistically significant worse impact after LTME was observed by QLQ-C30 in: Global Health Status (p= 0.05), Emotional Functioning (p= 0.021), Dyspnea (p= 0.008), Insomnia (p= 0.012), Appetite Loss (p= 0.014) and by QLQ-CR38 in Body Image (p= 0.05) and Defecation Problems (p= 0.001). At 1 year, the two groups were homogenous as assessed by QLQ-C30, whereas the QLQ-CR38 still showed better results of ELRR versus LTME in Body Image (p= 0.006), Defecation Problems (p= 0.01), and Weight Loss (p= 0.005). Based on the present series, in selected patients, earlier restoration of patients’ functions is observed after ELRR by TEM than after LTME.

At the end of March 2015 the onboard software configuration of the Astrorivelatore Gamma a Immagini Leggero (AGILE) satellite was modified in order to disable the veto signal of the anticoincidence shield for the minicalorimeter instrument. The motivation for such a change was the understanding that the dead time induced by the anticoincidence prevented the detection of a large fraction of Terrestrial Gamma‐Ray Flashes (TGFs). The configuration change was highly successful resulting in an increase of one order of magnitude in TGF detection rate. As expected, the largest fraction of the new events has short duration (<100 μs), and part of them has simultaneous association with lightning sferics detected by the World Wide Lightning Location Network. The new configuration provides the largest TGF detection rate surface density (TGFs/km2/yr) to date, opening prospects for improved correlation studies with lightning and atmospheric parameters on short spatial and temporal scales along the equatorial region. Tenfold improvement in TGF detection rate by AGILE is obtained after a major configuration changeThe sample is dead time‐free, with TGF durations as short as 20 μsThe relationship between TGF duration and likelihood of association with lightning is confirmed

Activated Protein C (APC) is a multifunctional serine protease, primarily known for its anticoagulant function in the coagulation system. Several studies have already elucidated its role in counteracting apoptosis and inflammation in cells, while significant effort is still ongoing for defining its involvement in sepsis. Earlier literature has shown that the antiseptic function of APC is mediated by its binding to leukocyte integrins, which is due to the presence of the integrin binding motif Arg-Gly-Asp at the N-terminus of the APC catalytic chain. Many natural mutants have been identified in patients with Protein C deficiency diagnosis including a variant of specificity pocket (Gly216Asp). In this work, we present a molecular model of the complex of APC with αVβ3 integrin obtained by protein–protein docking approach. A computational analysis of this variant is hereby presented, based on molecular dynamics and docking simulations, aiming at investigating the effects of the Gly216Asp mutation on the protein conformation and inferring its functional implications. Our study shows that such mutation is likely to impair the protease activity while preserving the overall protein fold. Moreover, superposition of the integrin binding motifs in wild-type and mutant forms suggests that the interaction with integrin can still occur and thus the mutant is likely to retain its antiseptic function related to the neutrophyl integrin binding. Therapeutic applications could result in this APC mutant which retains antiseptic function without anticoagulant side effects.

Endoluminal locoregional resection (ELRR) by transanal endoscopic microsurgery (TEM) is an alternative treatment option for T1N0rectal cancer and for selected patients with small T2N0rectal cancer after neoadjuvant radiochemotherapy (n-RCT). The N parameter may remain undefined after transanal surgery. This study aimed to evaluate the role of a modified sentinel lymph node technique to improve N staging that the authors named “nucleotide-guided mesorectal excision” (NGME).The study enrolled 41 patients (24 men and 17 women) with a mean age of 70.5 years. Preoperative staging identified dysplasia with no suspicion for cancer at imaging (n= 8), dysplasia with suspected malignancy at imaging (n= 15), no suspicion of malignancy at imaging after n-RCT (n= 2), cT1N0(n= 6), cT2N0(n= 6), cT3N0(n= 3), and cT3N1(n= 1). The patients underwent ELRR by TEM with NGME. Before surgery, 99m-technetium-marked nanocolloid was injected into the peritumoral submucosa. After resection, the residual defect was probed to detect residual radioactivity. If present, hot mesorectal fat was excised.With NGME, the mesorectal lymph node harvest increased from 0 to 10. Lymph nodes were isolated in the specimen or in hot mesorectal fat of 20 patients, 8 of whom had undergone n-RCT. The mean lymph node harvest was 2.75 ± 3.01 (range 1–10) in the irradiated patients and 2.91 ± 1.62 (range 1–6) in the nonirradiated patients (p= 0.87). The average number of lymph nodes in the irradiated patients was higher than in a previous historical series.The use of NGME during ELRR by TEM increases the lymph node harvest and may improve staging accuracy after transanal surgery.

A new approach for the synthesis of Y3Al2Ga3O12(YAGG) nanophosphors allowing the preparation of crystallites with sizes starting from 45 nm is presented. The controllability of the energy and trap density of the resulting material samples by annealing temperature was confirmed by thermoluminescence (TL) measurements. It has been shown that the annealing of samples at temperatures up to 1300 °C does not cause any substantial growth of crystallites, still remaining below 100 nm, but leads to changes in the activation energy of the persistent luminescence (PersL) process. On the other hand, annealing above 1400 °C results in grain growth on the submicron scale, which was confirmed by X-ray powder diffraction (XRPD) and electron transmission microscopy (TEM) measurements. In addition, with an increase in the molar ratio of urea to the total amount of metals used (R), qualitative changes are observed in the PersL process occurring from the excited states of Cr3+and Pr3+ions. This proves the influence of the synthesis process, in particular of the metal complexation at its initial stage, on the final structure ordering in the annealed materials. These observations are linked to previously reported defects in the YAGG structure, leading to PersL.

Angehörige von Patient(inn)en auf Intensivstationen befinden sich in einer belastenden Situation – gleichzeitig sind sie wichtig für Pflegende und Patient(inn)en, etwa bei der Prävention und Behandlung eines akuten Delirs. Für die Erarbeitung eines Konzeptes zur Nutzung der Angehörigenressourcen wurde eine systematische Literaturübersicht durchgeführt zur Fragestellung: Mit welchen Maßnahmen können Angehörige von erwachsenen Intensivpflegepatient(inn)en mit Delir in ihrer unterstützenden Rolle gefördert werden? Acht qualitative und zwei quantitative Studien konnten als relevant identifiziert werden. Durch den Einbezug in die Pflege gewinnen Angehörige Sicherheit und erweitern ihr Verständnis für die Situation. Informationen und Anleitung haben höhere Priorität als emotionale Unterstützung durch Pflegende. Patient(inn)en mit Delir können mithilfe ihrer Angehörigen einfacher kommunizieren und fühlen sich sicherer. Pflegende erhalten Informationen und können die Zusammenarbeit individuell gestalten, wobei zeitliche und personelle Engpässe als problematisch beschrieben werden. Die professionelle Unterstützung von Angehörigen durch Pflegende liegt in der Befriedigung ihrer Bedürfnisse sowie in der Anleitung bei pflegerischen Maßnahmen. Pflegende benötigen ebenfalls Unterstützung in der Begleitung der Angehörigen. Strukturelle Vorgaben sowie prozess- und handlungsbezogene Anweisungen helfen den Pflegenden, die Angehörigen systematisch einzubeziehen. Dies kann unterstützend sein in der Gewährleistung der Patient(inn)ensicherheit sowie bei der Prävention und Behandlung des Delirs.

Serious games present a promising opportunity for learning, but the genre still lacks methodologies and tools for efficient and low-cost production, particularly for teacher and domain experts. This article gives an authoring framework that aims to provide structured support, from content design to final implementation. In particular, we have abstracted a conceptual model—the SandBox Serious Game - which relies on a generalization of task-based learning theory. The model invites players to perform cognitive tasks contextually while exploring information-rich virtual environments. We consider it particularly suited for cultural heritage entertainment applications. The model defines games that are set in realistic virtual worlds enriched with embedded educational tasks, which we have implemented as minigames. This approach simplifies the authoring work, which can easily be supported by visual authoring tools for ontology-based urban 3D modeling and implementation tasks, thus allowing an approach similar to the mind-maps concept. We propose a top-down methodology for content preparation, starting from a city-level analysis down to the single points of interest and associated tasks, which are instances of simple predefined minigame/quiz typologies. We provide examples and discuss criteria for selecting task typologies according to the authors' cognitive targets. Finally, we discuss the results of a user test, which took place in a lab, aimed at verifying the acquisition of cultural heritage knowledge in a pleasant and engaging way. Games appear particularly suited for supporting the study of images, especially of iconography. Compared to reading text, a game forces the player to focus more strongly on problems, which favors knowledge acquisition and retention. Learning complex concepts requires an investigative attitude, which can be spurred by well-designed games. Good design involves usability, graphic appeal, appropriate content, and the presence of connections which a player must discover in the content. Players should be asked to pay attention to and reason about their whole game activity - including the relationships between the game content, the brief introduction, and concluding texts. More comprehensive tests are needed to better investigate the educational effectiveness—however, the first results are promising, especially in terms of user motivation and creation of new opportunities for learning about CH.

Cytomegalovirus (CMV) infection is the leading cause of congenital nongenetic sensorineural hearing loss (SNHL) and a major cause of prelingual SNHL that is not present at birth. Polymerase chain reaction (PCR) analysis of dried blood samples on the Guthrie card has been proposed as a sensitive and specific method to screen for congenital CMV infection.

mRNA vaccines BNT162b2 and mRNA1273 are highly effective in preventing SARS-CoV-2 infection and mortality in healthy adults. However, their immunogenicity in immunocompromised Multiple Myeloma (MM) patients is less clear.

Mancuso: Celgene: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Zamagni: Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers-Squibb: Honoraria; Janssen: Honoraria. Pantani: Amgen: Honoraria; Janssen: Honoraria. Rocchi: Amgen: Honoraria; GalxoSmithKline: Honoraria; Janssen: Honoraria. Rizzello: Amgen: Honoraria; GlaxoSmithKline: Honoraria; Sanofi: Honoraria. Tacchetti: Amgen: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria. Zinzani: JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; TG Therapeutics: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; ADC Therap.: Other; Beigene: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

ABSTRACTReal-time multiplex isothermal nucleic acid sequence-based amplification (NASBA) was developed to detect Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionellaspp. in respiratory specimens using the NucliSens Basic Kit (bioMe´rieux, Boxtel, The Netherlands). Oligonucleotide primers were derived from the M. pneumoniae, C. pneumoniae, and Legionella pneumophila16S rRNA. For real-time detection, molecular beacons were used. Specificity was established on a panel of bacterial strains. The analytical sensitivity of the assay was determined by testing dilutions of wild-type in vitro-generated RNA in water and dilutions of reference strains in lysis buffer or added to pools of respiratory specimens. Subsequently, a limited number of M. pneumoniae-, C. pneumoniae-, and L. pneumophila-positive and -negative clinical specimens were analyzed. Specific detection of the 16S rRNA of the three organisms was achieved. The analytical sensitivity of the multiplex NASBA on spiked respiratory specimens was slightly diminished compared to the results obtained with the single-target (mono) real-time assays. We conclude that the proposed real-time multiplex NASBA assay, although less sensitive than the real-time mono NASBA assay, is a promising tool for the detection of M. pneumoniae, C. pneumoniae, and Legionellaspp. in respiratory specimens, regarding handling, speed, and number of samples that can be analyzed in a single run.

Chronic allograft nephropathy (CAN) is characterized by deposition of extracellular matrix (ECM) in all renal compartments. PAI-1 seems to play a pivotal role in ECM turnover in CAN. Rapamycin has been shown to improve long-term graft survival in patients with CAN. The aim of the study was to evaluate the molecular mechanisms underlying the beneficial effects of rapamycin on CAN progression at glomerular and tubulointerstitial level.

ABSTRACTThe immunogenicity of a lipoylated peptide (lipo-P59) reproducing the membrane-proximal external region (MPER) of the transmembrane glycoprotein of feline immunodeficiency virus (FIV) was investigated with cats. In the attempt to mimic the context in which MPER is located within intact virions, lipo-P59 was administered in association with membrane-like micelles. Analyses showed that in this milieu, lipo-P59 had a remarkable propensity to be positioned at the membrane interface, displayed a large number of ordered structures folded in turn helices, and was as active as lipo-P59 alone at inhibiting FIV infectivity in vitro. The antibodies developed differed from the ones previously obtained by immunizing cats with the nonlipoylated version of the peptide (G. Freer, S. Giannecchini, A. Tissot, M. F. Bachmann, P. Rovero, P. F. Serres, and M. Bendinelli, Virology 322:360-369, 2004) in epitope specificity and in the fact that they bound FIV virions. However, they too lacked virus-neutralizing activity and actually enhanced FIV infectivity for lymphoid cell cultures. It is concluded that the use of MPER-reproducing oligopeptides is not a viable approach for vaccinating against FIV.

ABSTRACTThe objectives of this study were to evaluate the performance of the NucliSens easyMAG platform for nucleic acid extraction from different clinical specimens compared to NucliSens miniMAG platform and manual QIAGEN extraction. The NucliSens easyMAG and the NucliSens miniMAG showed equal performance on 215 throat swabs since real-time nucleic acid sequence-based amplification scored the same samples positive for Mycoplasma pneumoniae(n= 9) and Chlamydia pneumoniae(n= 5) RNAs, although internal control RNA was slightly better detected with the NucliSens easyMAG (99.3% versus 96.8%). NucliSens easyMAG extracted nucleic acids more efficiently (higher recovery and/or fewer inhibitors) compared to QIAGEN extraction by showing, on average, lower Ct values in real-time LightCycler PCR, although 4 individual specimen out of 45 were found positive only with QIAGEN. For nine M. pneumoniae-positive throat swabs, the mean difference in Ct values between NucliSens easyMAG extraction and QIAGEN extraction was -2.26 (range, -5.77 to +0.60); for the detection of five C. pneumoniae-positive throat swabs, the average difference in Ct values between the two methods was -3.38 (range, -6.62 to -2.02); and for the detection of cytomegalovirus in 24 blood samples, the mean difference in Ct values between the two methods was -0.95 (range, -5.51 to +1.68). The NucliSens easyMAG is considerably easier to perform, efficiently extracts nucleic acids from throat swabs and whole blood, is automated, and has high throughput.