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Background and purpose: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated. Methods: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP. Results: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory-predominant CIDP (7%), 10 motor CIDP (3%), and eight motor-predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F-wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor-predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory-predominant CIDP did. Conclusions: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients.

Background To assess the ability of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) clinical criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to include within their classification the whole spectrum of clinical heterogeneity of the disease and to define the clinical characteristics of the unclassifiable clinical forms. Methods The 2021 EAN/PNS clinical criteria for CIDP were applied to 329 patients fulfilling the electrodiagnostic (and in some cases also the supportive) criteria for the diagnosis of CIDP. Clinical characteristics were reviewed for each patient not strictly fulfilling the clinical criteria ('unclassifiable'). Results At study inclusion, 124 (37.5%) patients had an unclassifiable clinical presentation, including 110 (89%) with a typical CIDP-like clinical phenotype in whom some segments of the four limbs were unaffected by weakness ('incomplete typical CIDP'), 10 (8%) with a mild distal, symmetric, sensory or sensorimotor polyneuropathy confined to the lower limbs with cranial nerve involvement ('cranial nerve predominant CIDP') and 4 (1%) with a symmetric sensorimotor polyneuropathy limited to the proximal and distal areas of the lower limbs ('paraparetic CIDP'). Eighty-one (65%) patients maintained an unclassifiable presentation during the entire disease follow-up while 13 patients progressed to typical CIDP. Patients with the unclassifiable clinical forms compared with patients with typical CIDP had a milder form of CIDP, while there was no difference in the distribution patterns of demyelination. Conclusions A proportion of patients with CIDP do not strictly fulfil the 2021 EAN/PNS clinical criteria for diagnosis. These unclassifiable clinical phenotypes may pose diagnostic challenges and thus deserve more attention in clinical practice and research.

Major surgical societies advised using non-operative management of appendicitis and suggested against laparoscopy during the COVID-19 pandemic. The hypothesis is that a significant reduction in the number of emergent appendectomies was observed during the pandemic, restricted to complex cases. The study aimed to analyse emergent surgical appendectomies during pandemic on a national basis and compare it to the same period of the previous year. This is a multicentre, retrospective, observational study investigating the outcomes of patients undergoing emergent appendectomy in March–April 2019 vs March–April 2020. The primary outcome was the number of appendectomies performed, classified according to the American Association for the Surgery of Trauma (AAST) score. Secondary outcomes were the type of surgical technique employed (laparoscopic vs open) and the complication rates. One thousand five hundred forty one patients with acute appendicitis underwent surgery during the two study periods. 1337 (86.8%) patients met the inclusion criteria: 546 (40.8%) patients underwent surgery for acute appendicitis in 2020 and 791 (59.2%) in 2019. According to AAST, patients with complicated appendicitis operated in 2019 were 30.3% vs 39.9% in 2020 (p = 0.001). We observed an increase in the number of post-operative complications in 2020 (15.9%) compared to 2019 (9.6%) (p < 0.001). The following determinants increased the likelihood of complication occurrence: undergoing surgery during 2020 (+ 67%), the increase of a unit in the AAST score (+ 26%), surgery performed > 24 h after admission (+ 58%), open surgery (+ 112%) and conversion to open surgery (+ 166%). In Italian hospitals, in March and April 2020, the number of appendectomies has drastically dropped. During the first pandemic wave, patients undergoing surgery were more frequently affected by more severe appendicitis than the previous year's timeframe and experienced a higher number of complications. Trial registrat

En una visión ulterior, el ser humano ¿será capaz de capitalizar todos los adelantos científicos y tecnológicos? ¿Podrá aplicarla correctamente o derivara en contra de la humanidad? Aquí indefectiblemente debemos acercarnos a los valores éticos y morales que tiñen de colores el progreso de la ciencia. Diversos epistemólogos, filósofos han compartido manuscritos sobre el crecimiento del conocimiento en múltiples áreas científicas y la ética con la que se ven aplicados los mismos. En este trabajo se busca generar una reflexión de como el ser humano en función a la sociedad en la que existe, es capaz de razonar o madurar los cambios asociados a la ciencia y tecnología en función a los elementos que le fueron dados en la comunidad donde se produjo su desarrollo cognitivo. Comprender la forma en que el ser humano aplica la ciencia; para generar avances tecnológicos que mejoren la calidad de vida y para explorar nuevos mundos de conocimiento.

We report spectral and imaging performance of a pixelated CdZnTe detector custom designed for the \emph{MeVCube} project: a small Compton telescope on a CubeSat platform. \emph{MeVCube} is expected to cover the energy range between $200\;\mathrm{keV}$ and $4\;\mathrm{MeV}$, with performance comparable to the last generation of larger satellites. In order to achieve this goal, an energy resolution of few percent in full width at half maximum (FWHM) and a $3$-D spatial resolution of few millimeters for the individual detectors are needed. The severe power constraints present in small satellites require very low power read-out electronics for the detector. Our read-out is based on the VATA450.3 ASIC developed by \emph{Ideas}, with a power consumption of only $0.25\;\mathrm{mW/channel}$, which exhibits good performance in terms of dynamic range, noise and linearity. A $2.0\;\mathrm{cm} \times 2.0\;\mathrm{cm} \times 1.5\;\mathrm{cm}$ CdZnTe detector, with a custom $8 \times 8$ pixel anode structure read-out by a VATA450.3 ASIC, has been tested. A preliminary read-out system for the cathode, based on a discrete \emph{Amptek} A250F charge sensitive pre-amplifier and a DRS4 ASIC, has been implemented. An energy resolution around $3\%$ FWHM has been measured at a gamma energy of $662\;\mathrm{keV}$; at $200\;\mathrm{keV}$ the average energy resolution is $6.5\%$, decreasing to $\lesssim 2\%$ at energies above $1\;\mathrm{MeV}$. A $3$-D spatial resolution of $\approx 2\,\mathrm{mm}$ is achieved.

Despite the impressive progress achieved both by X-ray and gamma-ray observatories in the last few decades, the energy range between $\sim200\;\mathrm{keV}$ and $\sim50\;\mathrm{MeV}$ remains poorly explored. COMPTEL, on-board the Compton Gamma-Ray Observatory (CGRO, $1991$-$2000$), opened the MeV gamma-ray band as a new window to astronomy, performing the first all-sky survey in the energy range from $0.75$ to $30\;\mathrm{MeV}$. More than $20$ years after the de-orbit of CGRO, no successor mission is yet operating. Over the past years many concepts have been proposed, for new observatories exploring different configurations and imaging techniques; a selection of the most recent ones includes AMEGO, ETCC, GECCO and COSI. We propose here a novel concept for a Compton telescope based on the CubeSat standard, named MeVCube, with the advantages of small cost and relatively short development time. The scientific payload is based on two layers of pixelated Cadmium-Zinc-Telluride (CdZnTe) detectors, coupled with low-power read-out electronics (ASIC, VATA450.3). The performance of the read-out electronics and CdZnTe custom designed detectors have been measured extensively at DESY. The performance of the telescope is accessed through simulations: despite a small effective area limited to a few $\mathrm{cm}^{2}$, MeVCube can reach an angular resolution of $1.5^{\circ}$ and a sensitivity comparable to the one achieved by the last generation of large-scale satellites like COMPTEL and INTEGRAL. Combined with a large field-of-view and a moderate cost, MeVCube can be a powerful instrument for transient observations and searches of electromagnetic counterparts of gravitational wave events.

En una visión ulterior, el ser humano ¿será capaz de capitalizar todos los adelantos científicos y tecnológicos? ¿Podrá aplicarla correctamente o derivara en contra de la humanidad? Aquí indefectiblemente debemos acercarnos a los valores éticos y morales que tiñen de colores el progreso de la ciencia. Diversos epistemólogos, filósofos han compartido manuscritos sobre el crecimiento del conocimiento en múltiples áreas científicas y la ética con la que se ven aplicados los mismos. En este trabajo se busca generar una reflexión de como el ser humano en función a la sociedad en la que existe, es capaz de razonar o madurar los cambios asociados a la ciencia y tecnología en función a los elementos que le fueron dados en la comunidad donde se produjo su desarrollo cognitivo. Comprender la forma en que el ser humano aplica la ciencia; para generar avances tecnológicos que mejoren la calidad de vida y para explorar nuevos mundos de conocimiento.

En una visión ulterior, el ser humano ¿será capaz de capitalizar todos los adelantos científicos y tecnológicos? ¿Podrá aplicarla correctamente o derivara en contra de la humanidad? Aquí indefectiblemente debemos acercarnos a los valores éticos y morales que tiñen de colores el progreso de la ciencia. Diversos epistemólogos, filósofos han compartido manuscritos sobre el crecimiento del conocimiento en múltiples áreas científicas y la ética con la que se ven aplicados los mismos. En este trabajo se busca generar una reflexión de como el ser humano en función a la sociedad en la que existe, es capaz de razonar o madurar los cambios asociados a la ciencia y tecnología en función a los elementos que le fueron dados en la comunidad donde se produjo su desarrollo cognitivo. Comprender la forma en que el ser humano aplica la ciencia; para generar avances tecnológicos que mejoren la calidad de vida y para explorar nuevos mundos de conocimiento.

This research was conducted in the field of public key infrastructures (PKI). This sector is highly confidential and deals with managing security through encryption. The products in this area are technical: the user interface and user experience aspects are not prioritized and they are usually ignored or downplayed. Neglecting these aspects can lead to different ethical risks not only to the company but also to its customers. In the field of public key infrastructures, design is, therefore, a matter of ethical concern. The purpose of this research is to analyse what are the ethical risks and principles that should be taken into consideration when creating a design system for public key infrastructure products. To find an answer, the study was divided into 3 phases. A preliminary analysis was carried out to identify possible ethical principles, subsequently, two rounds of interviews were conducted with 8 employees of a leading PKI company. The scope of the interviews was to establish the relevance of these principles and identify the associated risks. The results suggest that the design system should take into account 6 ethical principles: transparency, inclusiveness and accessibility, autonomy, security and privacy, accountability and resilience. The principle of transparency can be applied to the design system through a clear user interface and simpler workflows while inclusiveness and accessibility can be tackled by considering even non-technical audits and people with disabilities during the design process. To make the user more autonomous, it is important to act on the workflow in order to reduce the use of external documentation and the possibility of managing automation in a simple way. Security and privacy are the foundations of PKI products and therefore user interface and experience should not in any way limit these principles, but rather facilitate the procedures necessary to make products safe. The tracking of the users’ actions is crucial in this field, Denna forskning utfördes inom området för public key infrastructures (PKI). Denna sektor är mycket konfidentiell och har att göra med hanteringen av säkerhet genom kryptering. Produkterna inom detta område är tekniska: användargränssnittet och användarupplevelseaspekterna prioriteras inte och de ignoreras eller förringas vanligtvis. Att se bort från dessa aspekter kan leda till olika etiska risker inte bara för företaget utan även för dess kunder. Inom området för public key infrastructure är design därför en fråga av etisk angelägenhet. Syftet med denna forskning är att analysera vilka etiska risker och principer som bör beaktas när man skapar ett designsystem för public key infrastructure. För att hitta ett svar delades studien upp i 3 faser. En preliminär analys genomfördes för att identifiera möjliga etiska principer, därefter genomfördes två omgångar av intervjuer med 8 anställda på ett ledande PKI-företag. Intervjuernas omfattning var att fastställa relevansen av dessa principer och identifiera de associerade riskerna. Resultaten tyder på att designsystemet bör ta hänsyn till 6 etiska principer: transparens, inkludering och tillgänglighet, autonomi, säkerhet och integritet, ansvarighet och motståndskraft. Principen om transparens kan appliceras på designsystemet genom ett tydligt användargränssnitt och enklare arbetsflöden samtidigt som inkludering och tillgänglighet kan hanteras genom att beakta även icke-tekniska revisioner och personer med funktionshinder under designprocessen. För att göra användaren mer självständig är det viktigt att vara verksam på arbetsflödet för att minska användningen av extern dokumentation och möjligheten att hantera automatisering på ett enkelt sätt. Säkerhet och integritet är grunden för PKI-produkter och därför bör användargränssnitt och erfarenhet inte på något sätt begränsa dessa principer, utan snarare underlätta de procedurer som krävs för att göra produkter säkra. Spårningen av användarnas handlingar är avgörande inom dett

En una visión ulterior, el ser humano ¿será capaz de capitalizar todos los adelantos científicos y tecnológicos? ¿Podrá aplicarla correctamente o derivara en contra de la humanidad? Aquí indefectiblemente debemos acercarnos a los valores éticos y morales que tiñen de colores el progreso de la ciencia. Diversos epistemólogos, filósofos han compartido manuscritos sobre el crecimiento del conocimiento en múltiples áreas científicas y la ética con la que se ven aplicados los mismos. En este trabajo se busca generar una reflexión de como el ser humano en función a la sociedad en la que existe, es capaz de razonar o madurar los cambios asociados a la ciencia y tecnología en función a los elementos que le fueron dados en la comunidad donde se produjo su desarrollo cognitivo. Comprender la forma en que el ser humano aplica la ciencia; para generar avances tecnológicos que mejoren la calidad de vida y para explorar nuevos mundos de conocimiento.

We report spectral and imaging performance of a pixelated CdZnTe detector custom designed for the MeVCube project: a small Compton telescope on a CubeSat platform. MeVCube is expected to cover the energy range between 200 keV and 4 MeV, with a sensitivity comparable to the one of the last generation of larger satellites. In order to achieve this goal, an energy resolution of few percent in full width at half maximum (FWHM) and a 3-D spatial resolution of few millimeters for the individual detectors are needed. The severe power constraints present in small satellites require very low power read-out electronics for the detector. Our read-out is based on the VATA450.3 ASIC developed by Ideas, with a power consumption of only 0.25 mW/channel, which exhibits good performance in terms of dynamic range, noise and linearity. A 2.0 cm× 2.0 cm× 1.5 cm CdZnTe detector, with a custom 8 × 8 pixel anode structure read-out by a VATA450.3 ASIC, has been tested. A preliminary read-out system for the cathode, based on a discrete Amptek A250F charge sensitive pre-amplifier and a DRS4 ASIC, has been implemented. An energy resolution around 3% FWHM has been measured at a gamma energy of 662 keV; at 200 keV the average energy resolution is 6.5%, decreasing to ≲ 2% at energies above 1 MeV. A 3-D spatial resolution of ≈ 2 mm is achieved in each dimension., Peer Reviewed

Trotz der beeindruckenden Fortschritte, die die Röntgen- und Gammastrahlenobservatorien in den letzten Jahrzehnten erzielt haben, ist der Energiebereich zwischen 200 keV und 50 MeV nach wie vor kaum erforscht. Diese Lücke, die in der Literatur oft als ``MeV-Lücke'' bezeichnet wird, ist nicht auf einen Mangel an überzeugender Wissenschaft zurückzuführen, sondern auf technische Herausforderungen und Nachweisschwierigkeiten, die mit MeV-Beobachtungen einhergehen. COMPTEL an Bord von CGRO (1991-2000) war das letzte Teleskop, das eine vollständige Durchmusterung des MeV-Himmels mit einer relativ bescheidenen Empfindlichkeit durchführte. Für die Zukunft sind zahlreiche Missionen vorgeschlagen worden, insbesondere AMEGO, die die Leistung von COMPTEL um mindestens eine Größenordnung verbessern sollen. Der Zeitrahmen für die Entwicklung, den Aufbau und den Start solch großer Missionen beträgt jedoch etwa 10 Jahre und ist mit erheblichen Kosten verbunden. In diesem Szenario könnte ein viel kleinerer Satellit, der sich der neuen Welle von schnellen, relativ kostengünstigen Weltraumforschungsmissionen anschließt, die durch CubeSats ermöglicht werden, in kürzerer Zeit rentabel sein. In dieser Arbeit werden die Verfügbarkeit und die Leistung eines Compton-Teleskops auf der Grundlage des CubeSat-Standards, genannt MeVCube, untersucht. Die Auswirkungen der Materialwahl und verschiedener CubeSat-Nutzlasten wurden durch Simulationen bewertet. Trotz der begrenzten Größe kann selbst ein kleines Teleskop, das auf einem CubeSat fliegt, den Energiebereich von Hunderten von keV bis zu einigen MeV mit einer Empfindlichkeit abdecken, die mit der der letzten Generation von Großmissionen wie COMPTEL und INTEGRAL vergleichbar ist. Es wurden auch experimentelle Messungen an Cadmium-Zink-Tellurid-Halbleiterdetektoren und einer für den Weltraumbetrieb geeigneten Ausleseelektronik mit geringem Stromverbrauch durchgeführt., Despite the impressive progresses achieved both by X-ray and gamma-ray observatories in the last decades, the energy range between 200 keV and 50 MeV remains poorly explored. This gap in coverage, often referred in literature as the ``MeV gap'', is not due to lack of compelling science, but instead to technical challenges and detection difficulties that comes with MeV observations. COMPTEL, on-board CGRO (1991-2000), was the last telescope to accomplish a complete survey of the MeV-sky with a relatively modest sensitivity. Many missions have been proposed for the future, most notably AMEGO, aiming to improve COMPTEL's performance by at least one order of magnitude. However, the timescale for development, assembly and launch of such large missions is around 10 years, with substantial costs. Looking at this scenario, a much smaller satellite, joining the new wave of rapid, relatively inexpensive space science missions enabled by CubeSats, may be profitable on a shorter time-scale. This thesis evaluates the availability and performance of a Compton telescope based on the CubeSat standard, named MeVCube. The impact of material choice and different CubeSat payloads has been evaluated through simulations. Despite the limited size, even a small telescope flying on a CubeSat can cover the energy range from hundreds of keV up to few MeVs with a sensitivity comparable to that of the last generation of large-scale missions like COMPTEL and INTEGRAL. Experimental measurements on Cadmium-Zinc-Telluride semiconductor detectors and low-power read-out electronics suitable for space operation have been performed as well.

This research was conducted in the field of public key infrastructures (PKI). This sector is highly confidential and deals with managing security through encryption. The products in this area are technical: the user interface and user experience aspects are not prioritized and they are usually ignored or downplayed. Neglecting these aspects can lead to different ethical risks not only to the company but also to its customers. In the field of public key infrastructures, design is, therefore, a matter of ethical concern. The purpose of this research is to analyse what are the ethical risks and principles that should be taken into consideration when creating a design system for public key infrastructure products. To find an answer, the study was divided into 3 phases. A preliminary analysis was carried out to identify possible ethical principles, subsequently, two rounds of interviews were conducted with 8 employees of a leading PKI company. The scope of the interviews was to establish the relevance of these principles and identify the associated risks. The results suggest that the design system should take into account 6 ethical principles: transparency, inclusiveness and accessibility, autonomy, security and privacy, accountability and resilience. The principle of transparency can be applied to the design system through a clear user interface and simpler workflows while inclusiveness and accessibility can be tackled by considering even non-technical audits and people with disabilities during the design process. To make the user more autonomous, it is important to act on the workflow in order to reduce the use of external documentation and the possibility of managing automation in a simple way. Security and privacy are the foundations of PKI products and therefore user interface and experience should not in any way limit these principles, but rather facilitate the procedures necessary to make products safe. The tracking of the users’ actions is crucial in this field, Denna forskning utfördes inom området för public key infrastructures (PKI). Denna sektor är mycket konfidentiell och har att göra med hanteringen av säkerhet genom kryptering. Produkterna inom detta område är tekniska: användargränssnittet och användarupplevelseaspekterna prioriteras inte och de ignoreras eller förringas vanligtvis. Att se bort från dessa aspekter kan leda till olika etiska risker inte bara för företaget utan även för dess kunder. Inom området för public key infrastructure är design därför en fråga av etisk angelägenhet. Syftet med denna forskning är att analysera vilka etiska risker och principer som bör beaktas när man skapar ett designsystem för public key infrastructure. För att hitta ett svar delades studien upp i 3 faser. En preliminär analys genomfördes för att identifiera möjliga etiska principer, därefter genomfördes två omgångar av intervjuer med 8 anställda på ett ledande PKI-företag. Intervjuernas omfattning var att fastställa relevansen av dessa principer och identifiera de associerade riskerna. Resultaten tyder på att designsystemet bör ta hänsyn till 6 etiska principer: transparens, inkludering och tillgänglighet, autonomi, säkerhet och integritet, ansvarighet och motståndskraft. Principen om transparens kan appliceras på designsystemet genom ett tydligt användargränssnitt och enklare arbetsflöden samtidigt som inkludering och tillgänglighet kan hanteras genom att beakta även icke-tekniska revisioner och personer med funktionshinder under designprocessen. För att göra användaren mer självständig är det viktigt att vara verksam på arbetsflödet för att minska användningen av extern dokumentation och möjligheten att hantera automatisering på ett enkelt sätt. Säkerhet och integritet är grunden för PKI-produkter och därför bör användargränssnitt och erfarenhet inte på något sätt begränsa dessa principer, utan snarare underlätta de procedurer som krävs för att göra produkter säkra. Spårningen av användarnas handlingar är avgörande inom dett

In an ulterior vision, the human being will you be able to reflect on all the scientific and technological advances? Will be able to apply it correctly or will it turn against humanity? Here we must unfailingly approach the ethical and moral values that colour the progress of science. Various epistemologists and philosophers have shared manuscripts on the growth of knowledge in multiples scientific areas and the ethics with which they are applied. This work tries to produce a reflection on how the human being in function of the society in which it exists, is able to make a thought over and mature the changes associated with science and technology based on the elements that were given to him in the community where their cognitive development occurred. Understand the way in which humans apply science and perform technological advances that improve the quality of life and to explore new worlds of knowledge, En una visión ulterior, el ser humano ¿será capaz de capitalizar todos los adelantos científicos y tecnológicos? ¿Podrá aplicarla correctamente o derivara en contra de la humanidad? Aquí indefectiblemente debemos acercarnos a los valores éticos y morales que tiñen de colores el progreso de la ciencia. Diversos epistemólogos, filósofos han compartido manuscritos sobre el crecimiento del conocimiento en múltiples áreas científicas y la ética con la que se ven aplicados los mismos. En este trabajo se busca generar una reflexión de como el ser humano en función a la sociedad en la que existe, es capaz de razonar o madurar los cambios asociados a la ciencia y tecnología en función a los elementos que le fueron dados en la comunidad donde se produjo su desarrollo cognitivo. Comprender la forma en que el ser humano aplica la ciencia; para generar avances tecnológicos que mejoren la calidad de vida y para explorar nuevos mundos de conocimiento.

We report spectral and imaging performance of a pixelated CdZnTe detector custom designed for the MeVCube project: a small Compton telescope on a CubeSat platform. MeVCube is expected to cover the energy range between 200 keV and 4 MeV, with a sensitivity comparable to the one of the last generation of larger satellites. In order to achieve this goal, an energy resolution of few percent in full width at half maximum (FWHM) and a 3-D spatial resolution of few millimeters for the individual detectors are needed. The severe power constraints present in small satellites require very low power read-out electronics for the detector. Our read-out is based on the VATA450.3 ASIC developed by Ideas, with a power consumption of only 0.25 mW/channel, which exhibits good performance in terms of dynamic range, noise and linearity. A 2.0 cm× 2.0 cm× 1.5 cm CdZnTe detector, with a custom 8 × 8 pixel anode structure read-out by a VATA450.3 ASIC, has been tested. A preliminary read-out system for the cathode, based on a discrete Amptek A250F charge sensitive pre-amplifier and a DRS4 ASIC, has been implemented. An energy resolution around 3% FWHM has been measured at a gamma energy of 662 keV; at 200 keV the average energy resolution is 6.5%, decreasing to ≲ 2% at energies above 1 MeV. A 3-D spatial resolution of ≈ 2 mm is achieved in each dimension., Peer Reviewed

Despite the impressive progress achieved both by X-ray and gamma-ray observatories in the last few decades, the energy range between ∼ 200 keV and ∼ 50 MeV remains poorly explored. COMPTEL, on-board the Compton Gamma-Ray Observatory (CGRO, 1991-2000), opened the MeV gamma-ray band as a new window to astronomy, performing the first all-sky survey in the energy range from 0.75 to 30 MeV. More than 20 years after the de-orbit of CGRO, no successor mission is yet operating. Over the past years many concepts have been proposed, for new observatories exploring different configurations and imaging techniques; a selection of the most recent ones includes AMEGO, ETCC, GECCO and COSI. We propose here a novel concept for a Compton telescope based on the CubeSat standard, named MeVCube, with the advantages of small cost and relatively short development time. The scientific payload is based on two layers of pixelated Cadmium-Zinc-Telluride (CdZnTe) detectors, coupled with low-power read-out electronics (ASIC, VATA450.3). The performance of the read-out electronics and CdZnTe custom designed detectors have been measured extensively at DESY [1]. The performance of the telescope is accessed through simulations: despite a small effective area limited to a few cm2, MeVCube can reach an angular resolution of 1.5° and a sensitivity comparable to the one achieved by the last generation of large-scale satellites like COMPTEL and INTEGRAL. Combined with a large field-of-view and a moderate cost, MeVCube can be a powerful instrument for transient observations and searches of electromagnetic counterparts of gravitational wave events., Peer Reviewed

The defining trait of magnetars, the most strongly magnetized neutron stars (NSs), is their transient activity in the X/$\gamma$-bands. In particular, many of them undergo phases of enhanced emission, the so-called outbursts, during which the luminosity rises by a factor $\sim$10$-$1000 in a few hours to then decay over months/years. Outbursts often exhibit a thermal spectrum, associated with the appearance of hotter regions on the surface of the star, which subsequently change in shape and cool down. Here we simulate the unfolding of a sudden, localized heat injection in the external crust of a NS with a 3D magneto-thermal evolution code, finding that this can reproduce the main features of magnetar outbursts. A full 3D treatment allows us to study for the first time the inherently asymmetric hot-spots which appear on the surface of the star as the result of the injection and to follow the evolution of their temperature and shape. We investigate the effects produced by different physical conditions in the heated region, highlighting in particular how the geometry of the magnetic field plays a key role in determining the properties of the event., Comment: 12 pages, 10 figures, accepted for publication in ApJ

Despite the impressive progress achieved both by X-ray and gamma-ray observatories in the last few decades, the energy range between $\sim200\;\mathrm{keV}$ and $\sim50\;\mathrm{MeV}$ remains poorly explored. COMPTEL, on-board the Compton Gamma-Ray Observatory (CGRO, $1991$-$2000$), opened the MeV gamma-ray band as a new window to astronomy, performing the first all-sky survey in the energy range from $0.75$ to $30\;\mathrm{MeV}$. More than $20$ years after the de-orbit of CGRO, no successor mission is yet operating. Over the past years many concepts have been proposed, for new observatories exploring different configurations and imaging techniques; a selection of the most recent ones includes AMEGO, ETCC, GECCO and COSI. We propose here a novel concept for a Compton telescope based on the CubeSat standard, named MeVCube, with the advantages of small cost and relatively short development time. The scientific payload is based on two layers of pixelated Cadmium-Zinc-Telluride (CdZnTe) detectors, coupled with low-power read-out electronics (ASIC, VATA450.3). The performance of the read-out electronics and CdZnTe custom designed detectors have been measured extensively at DESY. The performance of the telescope is accessed through simulations: despite a small effective area limited to a few $\mathrm{cm}^{2}$, MeVCube can reach an angular resolution of $1.5^{\circ}$ and a sensitivity comparable to the one achieved by the last generation of large-scale satellites like COMPTEL and INTEGRAL. Combined with a large field-of-view and a moderate cost, MeVCube can be a powerful instrument for transient observations and searches of electromagnetic counterparts of gravitational wave events., Comment: Accepted for publication in JCAP

We report spectral and imaging performance of a pixelated CdZnTe detector custom designed for the \emph{MeVCube} project: a small Compton telescope on a CubeSat platform. \emph{MeVCube} is expected to cover the energy range between $200\;\mathrm{keV}$ and $4\;\mathrm{MeV}$, with performance comparable to the last generation of larger satellites. In order to achieve this goal, an energy resolution of few percent in full width at half maximum (FWHM) and a $3$-D spatial resolution of few millimeters for the individual detectors are needed. The severe power constraints present in small satellites require very low power read-out electronics for the detector. Our read-out is based on the VATA450.3 ASIC developed by \emph{Ideas}, with a power consumption of only $0.25\;\mathrm{mW/channel}$, which exhibits good performance in terms of dynamic range, noise and linearity. A $2.0\;\mathrm{cm} \times 2.0\;\mathrm{cm} \times 1.5\;\mathrm{cm}$ CdZnTe detector, with a custom $8 \times 8$ pixel anode structure read-out by a VATA450.3 ASIC, has been tested. A preliminary read-out system for the cathode, based on a discrete \emph{Amptek} A250F charge sensitive pre-amplifier and a DRS4 ASIC, has been implemented. An energy resolution around $3\%$ FWHM has been measured at a gamma energy of $662\;\mathrm{keV}$; at $200\;\mathrm{keV}$ the average energy resolution is $6.5\%$, decreasing to $\lesssim 2\%$ at energies above $1\;\mathrm{MeV}$. A $3$-D spatial resolution of $\approx 2\,\mathrm{mm}$ is achieved., Comment: Accpted for publication in JINST

Despite the impressive progresses achieved both by X-ray and gamma-ray observatories in the last decades, the energy range between $\sim 200\,\mathrm{keV}$ and $\sim 50\,\mathrm{MeV}$ remains poorly explored. COMPTEL, on-board CGRO (1991-2000), was the last telescope to accomplish a complete survey of the MeV-sky with a relatively modest sensitivity. Missions like AMEGO have been proposed for the future, in order to fill this gap in observation; however, the time-scale for development and launch is about 10 years. On a shorter time-scale, a different approach may be profitable: MeV observations can be performed by a Compton telescope flying on a CubeSat. MeVCube is a 6U CubeSat concept currently under investigation at DESY, that could cover the energy range between hundreds of keV up to few MeVs with a sensitivity comparable to that of missions like COMPTEL and INTEGRAL. The Compton camera is based on pixelated Cadmium-Zinc-Telluride (CdZnTe) semiconductor detectors, coupled with low-power read-out electronics (ASIC, VATA450.3), ensuring a high detection efficiency and excellent energy resolution. In this work I will show measurements of the performance of a custom design CdZnTe detector and extrapolations of the expected telescope performance based on these measurements as well as simulations., Comment: Proceedings of the 37th International Cosmic Ray Conference (ICRC 2021)

Despite the impressive progresses achieved both by X-ray and gamma-ray observatories in the last decades, the energy range between $\sim 200\,\mathrm{keV}$ and $\sim 50\,\mathrm{MeV}$ remains poorly explored. COMPTEL, on-board CGRO (1991-2000), was the last telescope to accomplish a complete survey of the MeV-sky with a relatively modest sensitivity. Missions like AMEGO have been proposed for the future, in order to fill this gap in observation; however, the time-scale for development and launch is about 10 years. On a shorter time-scale, a different approach may be profitable: MeV observations can be performed by a Compton telescope flying on a CubeSat. MeVCube is a 6U CubeSat concept currently under investigation at DESY, that could cover the energy range between hundreds of keV up to few MeVs with a sensitivity comparable to that of missions like COMPTEL and INTEGRAL. The Compton camera is based on pixelated Cadmium-Zinc-Telluride (CdZnTe) semiconductor detectors, coupled with low-power read-out electronics (ASIC, VATA450.3), ensuring a high detection efficiency and excellent energy resolution. In this work I will show measurements of the performance of a custom design CdZnTe detector and extrapolations of the expected telescope performance based on these measurements as well as simulations., Comment: Proceedings of the 37th International Cosmic Ray Conference (ICRC 2021)

Background: Persistent critical illness (PerCI) is defined as an intensive care unit (ICU) admission lasting ≥ 10 days. The in-hospital complications associated with its development are poorly understood. Aims: To test whether PerCI is associated with a greater prevalence, rate and specific types of in-hospital complications. Methods: Single-centre, retrospective, observational case-control study. Results: We studied 1200 patients admitted to a tertiary ICU from 2010 to 2015. Median ICU length of stay was 16 days (interquartile range [IQR], 12-23) for PerCI patients v 2.3 days (IQR, 1.1-3.7) for controls, and median hospital length of stay was 41 days (IQR, 22-75) v 8 days (IQR, 4-17) respectively. A greater proportion of PerCI patients received acute renal replacement therapy (37% v 6.8%) or underwent reintubation (17% v 1%) and/or tracheostomy (36% v 0.6%); P < 0.0001. Despite these complications, PerCI patients had similar hospital mortality (29% v 27%; P = 0.53). PerCI patients experienced a greater absolute number of complications (12.1 v 4.0 complications per patient; P < 0.0001) but had fewer exposure-adjusted complications (202 v 272 complications per 1000 hospital bed-days; P < 0.001) and a particularly high overall prevalence of specific complications. Conclusions: PerCI patients experience a higher prevalence, but not a higher rate, of exposure-adjusted complications. Some of these complications appear amenable to prevention, helping to define intervention targets in patients at risk of PerCI. Funding: Austin Hospital Intensive Care Trust Fund.

Objective: To map the clinical pharmacy services conducted in Brazil, their characteristics, outcomes, and process measures in general population, as well as the assessment of the clinical impact on people with cardiometabolic diseases (cardiovascular diseases and metabolic diseases). Methods: A systematic scoping review and meta-analysis were conducted. The electronic searches were re-run in March 2020. To the clinical impact assessment, meta-analyses of cardiometabolic outcomes (i.e., change of systolic (SBP) and diastolic blood pressure (DBP), triglycerides, total cholesterol, glycated hemoglobin (HbA1c), fasting glycemia, LDL-, and HDL-cholesterol) were led. The risk of bias was assessed with the Cochrane Collaboration tools. Results: 71 studies were identified (7,402 patients), being the majority quasi-experimental studies (n=41) and published by research groups of Southeast Brazil (n=33). Medication therapy management (n=62) was the most frequent clinical pharmacy service, performed on outpatient setting (n=45), with adults or elderly people (n=58) with hypertension (n=18) or diabetes (n=10). Process measures (n=58) (e.g. resolution of drug related-problem) were widely used as indicator, followed by clinical (n=44) (e.g. change in SBP), humanistic (n=12) (e.g. change in quality-of-life score assessed by Short-Form 36 Health Survey Questionnaire), and economic outcomes (n=3) (incremental cost-effectiveness ratio for reduction in HbA1c). Regarding the assessment of clinical impact of the services, 20 studies were included in meta-analyses, showing improvement in most cardiometabolic outcomes when considered individual studies. However, the evidence presents high risk of bias, high heterogeneity (median 67-90%) and imprecision, contributing to wide prediction intervals and low reliability. Conclusions: A predominance of studies on cardiometabolic diseases, process measures, and clinical outcomes were identified. Considering the assessment of the clinical impact o

This paper examines the macroeconomic effects of rising migration uncertainty in four advanced economies (i.e. US, UK, Germany and France). Migration uncertainty is first captured by the Migration Policy Uncertainty (MPUI) and the Migration Fear (MFI) news-based indexes developed by Baker et al. (Immigration fears and policy uncertainty, 2015), and then by a novel Google Trend Migration Uncertainty Index (GTMU) based on the frequency of Internet searches for the term ‘immigration’. VAR investigations suggest that the macroeconomic implications of rising migration uncertainty differ across countries. Moreover, news-based and Google search-based migration fear shocks generate different macroeconomic effects. For instance, in the US (France), MPUI, MFI and GTMU shocks all improve (undermine) production and labour market conditions in the medium run. For Germany and the UK, mixed evidence is found, suggesting that increasing media attention on migration phenomena and rising population's interest in migration-related issues influence people's mood differently. The observed heterogeneity in the macroeconomic effects of rising migration uncertainty can be explained by cross-country gaps in (a) the level of labour market rigidity, (b) the degree of people's happiness and life satisfaction and (c) the percentage of graduates.

BACKGROUND: Genomic initiatives such as The Cancer Genome Atlas (TCGA) contain data from -omics profiling of thousands of tumor samples, which may be used to decipher cancer signaling, and related alterations. Managing and analyzing data from large-scale projects, such as TCGA, is a demanding task. It is difficult to dissect the high complexity hidden in genomic data and to account for inter-tumor heterogeneity adequately.METHODS: In this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patients from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC).RESULTS: We used the gene expression data to identify co-expression modules and differentially expressed genes to discriminate between LUAD and LUSC. We identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, along with two dual role genes. Our results have been validated against other transcriptomics data of lung cancer patients.CONCLUSIONS: Our integrative approach allowed us to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC might be linked to the activation of three oncogenic pathways, which promote the evasion of the antitumor immune response. Collectively, our results provide new future directions for the design of target therapies in lung cancer.

Sunlit snow is highly photochemically active and plays a key role in the exchange of gas phase species between the cryosphere and the atmosphere. Here, we investigate the behaviour of two selected species in surface snow: mercury (Hg) and iodine (I). Hg can deposit year-round and accumulate in the snowpack. However, photo-induced re-emission of gas phase Hg from the surface has been widely reported. Iodine is active in atmospheric new particle formation, especially in the marine boundary layer, and in the destruction of atmospheric ozone. It can also undergo photochemical re-emission. Although previous studies indicate possible post-depositional processes, little is known about the diurnal behaviour of these two species and their interaction in surface snow. The mechanisms are still poorly constrained, and no field experiments have been performed in different seasons to investigate the magnitude of re-emission processes Three sampling campaigns conducted at an hourly resolution for 3 d each were carried out near Ny-Ålesund (Svalbard) to study the behaviour of mercury and iodine in surface snow under different sunlight and environmental conditions (24 h darkness, 24 h sunlight and day–night cycles). Our results indicate a different behaviour of mercury and iodine in surface snow during the different campaigns. The day–night experiments demonstrate the existence of a diurnal cycle in surface snow for Hg and iodine, indicating that these species are indeed influenced by the daily solar radiation cycle. Differently, bromine did not show any diurnal cycle. The diurnal cycle also disappeared for Hg and iodine during the 24 h sunlight period and during 24 h darkness experiments supporting the idea of the occurrence (absence) of a continuous recycling or exchange at the snow–air interface. These results demonstrate that this surface snow recycling is seasonally dependent, through sunlight. They also highlight the non-negligible role that snowpack emissions have on ambient a

Sunlit snow is highly photochemically active and plays a key role in the exchange of gas phase species between the cryosphere and the atmosphere. Here, we investigate the behaviour of two selected species in surface snow: mercury (Hg) and iodine (I). Hg can deposit year-round and accumulate in the snowpack. However, photo-induced re-emission of gas phase Hg from the surface has been widely reported. Iodine is active in atmospheric new particle formation, especially in the marine boundary layer, and in the destruction of atmospheric ozone. It can also undergo photochemical re-emission. Although previous studies indicate possible post-depositional processes, little is known about the diurnal behaviour of these two species and their interaction in surface snow. The mechanisms are still poorly constrained, and no field experiments have been performed in different seasons to investigate the magnitude of re-emission processes Three sampling campaigns conducted at an hourly resolution for 3 d each were carried out near Ny-Ålesund (Svalbard) to study the behaviour of mercury and iodine in surface snow under different sunlight and environmental conditions (24 h darkness, 24 h sunlight and day–night cycles). Our results indicate a different behaviour of mercury and iodine in surface snow during the different campaigns. The day–night experiments demonstrate the existence of a diurnal cycle in surface snow for Hg and iodine, indicating that these species are indeed influenced by the daily solar radiation cycle. Differently, bromine did not show any diurnal cycle. The diurnal cycle also disappeared for Hg and iodine during the 24 h sunlight period and during 24 h darkness experiments supporting the idea of the occurrence (absence) of a continuous recycling or exchange at the snow–air interface. These results demonstrate that this surface snow recycling is seasonally dependent, through sunlight. They also highlight the non-negligible role that snowpack emissions have on ambient a

Background: Although the management of hyperkalemia follows expert guidelines, treatment approaches are based on traditionally accepted practice standards. New drugs have been assessed such as sodium zirconium cyclosilicate and patiromer; however, their safety and efficacy or effectiveness have not yet been compared to traditional pharmacotherapy. Objective: The present systematic review had the purpose to evaluate the efficacy, effectiveness, and safety of hyperkalemia pharmacotherapies. Methods: PubMed, LILACS, Cochrane Library, and ClinicalTrials were searched through November 2018. Clinical trial, cohort and case-control were searched. The risk of bias (RoB v2.0 and ROBINS-I) and quality of evidence (GRADE) at the level of outcomes were assessed. Results: Sixteen clinical trials and one retrospective cohort were identified regarding efficacy and safety of 24 different alternatives. The management of hyperkalemia remains empirical and off-label, since sodium zirconium cyclosilicate and patiromer are not available in several countries and further studies are required to assess efficacy, effectiveness and safety. Sodium or calcium polystyrene sulfonate (moderate confidence), sodium zirconium cyclosilicate (moderate confidence), and insulin plus dextrose (moderate confidence) showed superior efficacy to, respectively, placebo, no treatment, placebo, and dextrose. Other therapies (low confidence) showed similar efficacy compared to active or inactive alternatives. Most of the adverse events reported were nonspecific, so it was not possible to assign the cause and to classify as defined or probable. Conclusions: Comparative cohort and case-control studies are need to evaluate the safety and effectiveness of new and traditional pharmacotherapies to support the development of guidelines about acute and chronic hyperkalemia, with high-quality evidence.

BACKGROUND: Genomic initiatives such as The Cancer Genome Atlas (TCGA) contain data from -omics profiling of thousands of tumor samples, which may be used to decipher cancer signaling, and related alterations. Managing and analyzing data from large-scale projects, such as TCGA, is a demanding task. It is difficult to dissect the high complexity hidden in genomic data and to account for inter-tumor heterogeneity adequately.METHODS: In this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patients from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC).RESULTS: We used the gene expression data to identify co-expression modules and differentially expressed genes to discriminate between LUAD and LUSC. We identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, along with two dual role genes. Our results have been validated against other transcriptomics data of lung cancer patients.CONCLUSIONS: Our integrative approach allowed us to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC might be linked to the activation of three oncogenic pathways, which promote the evasion of the antitumor immune response. Collectively, our results provide new future directions for the design of target therapies in lung cancer.

The advent of Next-Generation Sequencing (NGS) technologies has opened new perspectives in deciphering the genetic mechanisms underlying complex diseases. Nowadays, the amount of genomic data is massive and substantial efforts and new tools are required to unveil the information hidden in the data. The Genomic Data Commons (GDC) Data Portal is a platform that contains different genomic studies including the ones from The Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiatives, accounting for more than 40 tumor types originating from nearly 30000 patients. Such platforms, although very attractive, must make sure the stored data are easily accessible and adequately harmonized. Moreover, they have the primary focus on the data storage in a unique place, and they do not provide a comprehensive toolkit for analyses and interpretation of the data. To fulfill this urgent need, comprehensive but easily accessible computational methods for integrative analyses of genomic data that do not renounce a robust statistical and theoretical framework are required. In this context, the R/Bioconductor package TCGAbiolinks was developed, offering a variety of bioinformatics functionalities. Here we introduce new features and enhancements of TCGAbiolinks in terms of i) more accurate and flexible pipelines for differential expression analyses, ii) different methods for tumor purity estimation and filtering, iii) integration of normal samples from other platforms iv) support for other genomics datasets, exemplified here by the TARGET data. Evidence has shown that accounting for tumor purity is essential in the study of tumorigenesis, as these factors promote confounding behavior regarding differential expression analysis. With this in mind, we implemented these filtering procedures in TCGAbiolinks. Moreover, a limitation of some of the TCGA datasets is the unavailability or paucity of corresponding normal samples. We

Sunlit snow is highly photochemically active and plays a key role in the exchange of gas phase species between the cryosphere and the atmosphere. Here, we investigate the behaviour of two selected species in surface snow: mercury (Hg) and iodine (I). Hg can deposit year-round and accumulate in the snowpack. However, photo-induced re-emission of gas phase Hg from the surface has been widely reported. Iodine is active in atmospheric new particle formation, especially in the marine boundary layer, and in the destruction of atmospheric ozone. It can also undergo photochemical re-emission. Although previous studies indicate possible post-depositional processes, little is known about the diurnal behaviour of these two species and their interaction in surface snow. The mechanisms are still poorly constrained, and no field experiments have been performed in different seasons to investigate the magnitude of re-emission processes Three sampling campaigns conducted at an hourly resolution for 3 d each were carried out near Ny-Ålesund (Svalbard) to study the behaviour of mercury and iodine in surface snow under different sunlight and environmental conditions (24 h darkness, 24 h sunlight and day-night cycles). Our results indicate a different behaviour of mercury and iodine in surface snow during the different campaigns. The day-night experiments demonstrate the existence of a diurnal cycle in surface snow for Hg and iodine, indicating that these species are indeed influenced by the daily solar radiation cycle. Differently, bromine did not show any diurnal cycle. The diurnal cycle also disappeared for Hg and iodine during the 24 h sunlight period and during 24 h darkness experiments supporting the idea of the occurrence (absence) of a continuous recycling or exchange at the snow-air interface. These results demonstrate that this surface snow recycling is seasonally dependent, through sunlight. They also highlight the non-negligible role that snowpack emissions have on ambient a

The advent of Next-Generation Sequencing (NGS) technologies has opened new perspectives in deciphering the genetic mechanisms underlying complex diseases. Nowadays, the amount of genomic data is massive and substantial efforts and new tools are required to unveil the information hidden in the data. The Genomic Data Commons (GDC) Data Portal is a platform that contains different genomic studies including the ones from The Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiatives, accounting for more than 40 tumor types originating from nearly 30000 patients. Such platforms, although very attractive, must make sure the stored data are easily accessible and adequately harmonized. Moreover, they have the primary focus on the data storage in a unique place, and they do not provide a comprehensive toolkit for analyses and interpretation of the data. To fulfill this urgent need, comprehensive but easily accessible computational methods for integrative analyses of genomic data that do not renounce a robust statistical and theoretical framework are required. In this context, the R/Bioconductor package TCGAbiolinks was developed, offering a variety of bioinformatics functionalities. Here we introduce new features and enhancements of TCGAbiolinks in terms of i) more accurate and flexible pipelines for differential expression analyses, ii) different methods for tumor purity estimation and filtering, iii) integration of normal samples from other platforms iv) support for other genomics datasets, exemplified here by the TARGET data. Evidence has shown that accounting for tumor purity is essential in the study of tumorigenesis, as these factors promote confounding behavior regarding differential expression analysis. With this in mind, we implemented these filtering procedures in TCGAbiolinks. Moreover, a limitation of some of the TCGA datasets is the unavailability or paucity of corresponding normal samples. We thu, SCOPUS: ar.j, info:eu-repo/semantics/published

© 2019 Background: Randomised clinical trials (RCTs) and observational studies have reported adverse events that preclude the use of disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS) in the long term or in specific populations, however, little is known about the relationship between the use of DMTs and frequency of undesirable events. We aimed to conduct a systematic review and network meta-analyses (NMAs) of RCTs and observational studies to synthesise the evidence on the safety of all available DMTs for patients with RRMS. Methods: PubMed, Scopus and a manual search were performed. Bayesian NMAs of safety outcomes reported in RCTs and observational studies assessing DMTs as monotherapies were conducted. Results: Forty-seven studies were included in the systematic review. Considering all studies, 368 and 149 different safety outcomes were reported for at least one study and two studies, respectively. Considering clinical trials, 22 NMAs were conducted for 16 outcomes. Regarding geometry metrics, the median number of studies, DMTs, common comparator, strong edge, and patients were 5 (IQR 5–9), 5 (IQR 4–8), 44%, 33%, and 3998 (IQR 3380–6761). In summary, most comparisons showed similar risk of safety events for DMTs and placebo for all outcomes. Considering cohort studies, only three meta-analyses were conducted. Conclusion: Safety outcomes are poorly reported in primary studies of DMTs in RRMS, precluding the conduction of robust meta-analyses. Therefore, the current available data on safety of these drugs is not contributing to regulatory and clinical decision making, with adverse event reports underbalanced compared to efficacy outcomes.

© 2019 Background: Randomised clinical trials (RCTs) and observational studies have reported adverse events that preclude the use of disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS) in the long term or in specific populations, however, little is known about the relationship between the use of DMTs and frequency of undesirable events. We aimed to conduct a systematic review and network meta-analyses (NMAs) of RCTs and observational studies to synthesise the evidence on the safety of all available DMTs for patients with RRMS. Methods: PubMed, Scopus and a manual search were performed. Bayesian NMAs of safety outcomes reported in RCTs and observational studies assessing DMTs as monotherapies were conducted. Results: Forty-seven studies were included in the systematic review. Considering all studies, 368 and 149 different safety outcomes were reported for at least one study and two studies, respectively. Considering clinical trials, 22 NMAs were conducted for 16 outcomes. Regarding geometry metrics, the median number of studies, DMTs, common comparator, strong edge, and patients were 5 (IQR 5–9), 5 (IQR 4–8), 44%, 33%, and 3998 (IQR 3380–6761). In summary, most comparisons showed similar risk of safety events for DMTs and placebo for all outcomes. Considering cohort studies, only three meta-analyses were conducted. Conclusion: Safety outcomes are poorly reported in primary studies of DMTs in RRMS, precluding the conduction of robust meta-analyses. Therefore, the current available data on safety of these drugs is not contributing to regulatory and clinical decision making, with adverse event reports underbalanced compared to efficacy outcomes.

BACKGROUND: Genomic initiatives such as The Cancer Genome Atlas (TCGA) contain data from -omics profiling of thousands of tumor samples, which may be used to decipher cancer signaling, and related alterations. Managing and analyzing data from large-scale projects, such as TCGA, is a demanding task. It is difficult to dissect the high complexity hidden in genomic data and to account for inter-tumor heterogeneity adequately.METHODS: In this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patients from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC).RESULTS: We used the gene expression data to identify co-expression modules and differentially expressed genes to discriminate between LUAD and LUSC. We identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, along with two dual role genes. Our results have been validated against other transcriptomics data of lung cancer patients.CONCLUSIONS: Our integrative approach allowed us to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC might be linked to the activation of three oncogenic pathways, which promote the evasion of the antitumor immune response. Collectively, our results provide new future directions for the design of target therapies in lung cancer.

The advent of Next-Generation Sequencing (NGS) technologies has opened new perspectives in deciphering the genetic mechanisms underlying complex diseases. Nowadays, the amount of genomic data is massive and substantial efforts and new tools are required to unveil the information hidden in the data. The Genomic Data Commons (GDC) Data Portal is a platform that contains different genomic studies including the ones from The Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiatives, accounting for more than 40 tumor types originating from nearly 30000 patients. Such platforms, although very attractive, must make sure the stored data are easily accessible and adequately harmonized. Moreover, they have the primary focus on the data storage in a unique place, and they do not provide a comprehensive toolkit for analyses and interpretation of the data. To fulfill this urgent need, comprehensive but easily accessible computational methods for integrative analyses of genomic data that do not renounce a robust statistical and theoretical framework are required. In this context, the R/Bioconductor package TCGAbiolinks was developed, offering a variety of bioinformatics functionalities. Here we introduce new features and enhancements of TCGAbiolinks in terms of i) more accurate and flexible pipelines for differential expression analyses, ii) different methods for tumor purity estimation and filtering, iii) integration of normal samples from other platforms iv) support for other genomics datasets, exemplified here by the TARGET data. Evidence has shown that accounting for tumor purity is essential in the study of tumorigenesis, as these factors promote confounding behavior regarding differential expression analysis. With this in mind, we implemented these filtering procedures in TCGAbiolinks. Moreover, a limitation of some of the TCGA datasets is the unavailability or paucity of corresponding normal samples. We

Nitric oxide (NO) plays an essential role in redox signaling in normal and pathological cellular conditions. In particular, it is well known to react in vivo with cysteines by the so-called S-nitrosylation reaction. S-nitrosylation is a selective and reversible post-translational modification that exerts a myriad of different effects, such as the modulation of protein conformation, activity, stability, and biological interaction networks. We have appreciated, over the last years, the role of S-nitrosylation in normal and disease conditions. In this context, structural and computational studies can help to dissect the complex and multifaceted role of this redox post-translational modification. In this review article, we summarized the current state-of-the-art on the mechanism of S-nitrosylation, along with the structural and computational studies that have helped to unveil its effects and biological roles. We also discussed the need to move new steps forward especially in the direction of employing computational structural biology to address the molecular and atomistic details of S-nitrosylation. Indeed, this redox modification has been so far an underappreciated redox post-translational modification by the computational biochemistry community. In our review, we primarily focus on S-nitrosylated proteins that are attractive cancer targets due to the emerging relevance of this redox modification in a cancer setting.

Nitric oxide (NO) plays an essential role in redox signaling in normal and pathological cellular conditions. In particular, it is well known to react in vivo with cysteines by the so-called S-nitrosylation reaction. S-nitrosylation is a selective and reversible post-translational modification that exerts a myriad of different effects, such as the modulation of protein conformation, activity, stability, and biological interaction networks. We have appreciated, over the last years, the role of S-nitrosylation in normal and disease conditions. In this context, structural and computational studies can help to dissect the complex and multifaceted role of this redox post-translational modification. In this review article, we summarized the current state-of-the-art on the mechanism of S-nitrosylation, along with the structural and computational studies that have helped to unveil its effects and biological roles. We also discussed the need to move new steps forward especially in the direction of employing computational structural biology to address the molecular and atomistic details of S-nitrosylation. Indeed, this redox modification has been so far an underappreciated redox post-translational modification by the computational biochemistry community. In our review, we primarily focus on S-nitrosylated proteins that are attractive cancer targets due to the emerging relevance of this redox modification in a cancer setting.

OBJECTIVE: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome. DESIGN: Experimental study. SETTING: Animal research laboratory. SUBJECTS: Ten pigs, 35 ± 5.2 kg. INTERVENTIONS: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves. MEASUREMENTS AND MAIN RESULTS: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 ± 94 to 444 ± 115 dyn.s.cm and from 0.27 ± 0.14 to 0.62 ± 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 ± 0.86 to 1.48 ± 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 ± 0.07 vs 0.14 ± 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 ± 83 vs 378 ± 79 dyn.s.cm, p = 0.033, and vs 450 ± 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 ± 0.08 vs 0.50 ± 0.15 mm Hg/mL, p = 0.04, and vs 0.61 ± 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 ± 0.17 vs 0.48 ± 0.10, p = 0.024, and vs 0.53 ± 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively. CONCL

BACKGROUND: In critically ill patients with permissive hyperglycemia, it is uncertain whether exogenous insulin administration suppresses or enhances c-peptide secretion (a marker of pancreatic beta-cell response). We aimed to explore this effect in patients with type 2 diabetes. METHODS: We prospectively enrolled a cohort of 45 critically ill patients with type 2 diabetes managed according to a liberal glucose protocol (target blood glucose 10-14 mmol/l). We recorded the administration of insulin and oral hypoglycemic agents and measured plasma c-peptide as surrogate marker of endogenous insulin secretion on the first two consecutive days in ICU. RESULTS: Overall, 20 (44.4%) patients required insulin to achieve target blood glucose. Insulin-treated patients had higher glycated hemoglobin A1c, more premorbid insulin-requiring type 2 diabetes, and greater blood glucose levels but lower c-peptide levels on admission. Premorbid insulin-requiring diabetes was independently associated with lower admission c-peptide, whereas greater plasma creatinine was independently associated with higher levels. Increases in c-peptide were positively correlated with an increase in blood glucose both in patients who did (r = 0.54, P = 0.01) and did not (r = 0.56, P = 0.004) receive insulin. However, insulin administration was independently associated with a greater increase in c-peptide (P = 0.04). This association was not modified by the use of oral insulin secretagogues. CONCLUSIONS: C-peptide, a marker of beta-cell response, responds to and is influenced by glycemia and renal function in critically ill patients with type 2 diabetes. In addition, in our cohort, exogenous insulin administration was associated with a greater increase in c-peptide in response to hyperglycemia. Trial Registration Australian New Zealand Clinical Trials Registry (ACTRN12615000216516).

Antiobesity pharmacotherapy remains the main point of disagreement among both scientists and regulators. This is probably due to small sample sizes, high levels of heterogeneity, and low methodological quality. For many years, Brazil was one of the largest consumers of appetite suppressants worldwide, with evidence of irrational use of this drug class. Therefore, the country was the scene of a debate that divided the Brazilian Health Surveillance Agency (Anvisa - Agência Nacional de Vigilância Sanitáia) and medical societies over the maintenance record of diethylpropion, mazindol and fenproporex. In this context, this commentary presents new arguments to contribute to the discussion, as well as recommendations for future studies.

To investigate the scale structure and psychometrics of the EORTC chemotherapy-induced peripheral neuropathy module (QLQ-CIPN20).Using confirmatory factor analyses (CFA), we tested two hypothesized scale structure models of the QLQ-CIPN20 in 473 patients with non-small cell lung cancer, 281 patients with heterogeneous cancer diagnoses, and 500 patients with colorectal cancer. We also modeled the two hypothesized models as bi-factor models. These included a general factor, in addition to the specific domain factors. Additional models were investigated with exploratory factor analysis (EFA). Known groups validity was evaluated where justified.CFA could not confirm the two hypothesized models (Model 1: CFI < 0.926; TLI < 0.914; RMSEA > 0.077 and Model 2: CFI < 0.906; TLI < 0.887; RMSEA > 0.105) in any of the three samples. Including a general factor to these two hypothesized models to produce a bi-factor model also did not yield satisfactory results. Using EFA, we identified four different factor structures in the three samples that were unstable due to cross loadings of the items. When scoring the QLQ-CIPN20 as a simple, additive checklist evidence was found for known groups validity in the first two samples based on Common Toxicity Criteria (CTC-AE), and in the third sample based on exposure to CIPN-inducing chemotherapy.Neither CFA nor EFA yielded support for a stable subscale structure for the QLQ-CIPN20. Scoring the questionnaire as a simple additive checklist results in acceptable validity.

Purpose: To investigate the scale structure and psychometrics of the EORTC chemotherapy-induced peripheral neuropathy module (QLQ-CIPN20). Methods: Using confirmatory factor analyses (CFA), we tested two hypothesized scale structure models of the QLQ-CIPN20 in 473 patients with non-small cell lung cancer, 281 patients with heterogeneous cancer diagnoses, and 500 patients with colorectal cancer. We also modeled the two hypothesized models as bi-factor models. These included a general factor, in addition to the specific domain factors. Additional models were investigated with exploratory factor analysis (EFA). Known groups validity was evaluated where justified. Results: CFA could not confirm the two hypothesized models (Model 1: CFI < 0.926; TLI < 0.914; RMSEA > 0.077 and Model 2: CFI < 0.906; TLI < 0.887; RMSEA > 0.105) in any of the three samples. Including a general factor to these two hypothesized models to produce a bi-factor model also did not yield satisfactory results. Using EFA, we identified four different factor structures in the three samples that were unstable due to cross loadings of the items. When scoring the QLQ-CIPN20 as a simple, additive checklist evidence was found for known groups validity in the first two samples based on Common Toxicity Criteria (CTC-AE), and in the third sample based on exposure to CIPN-inducing chemotherapy. Conclusions: Neither CFA nor EFA yielded support for a stable subscale structure for the QLQ-CIPN20. Scoring the questionnaire as a simple additive checklist results in acceptable validity.