Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism

The histone demethylase KDM1A is a multi- faceted regulator of vital developmental processes, including mesodermal and cardiac tube formation during gastrulation. However, it is unknown whether the fine-tuning of KDM1A splicing isoforms, already shown to regulate neuronal maturation, is crucial for the specification and maintenance of cell identity during cardiogenesis. Here, we discovered a temporal modulation of ubKDM1A and KDM1A+2a during human and mice fetal cardiac development and evaluated their impact on the regulation of cardiac differentiation. We revealed a severely impaired cardiac differentiation in KDM1A(-/-) hESCs that can be rescued by re-expressing ubKDM1A or catalytically impaired ubKDM1A-K661A, but not by KDM1A+2a or KDM1A+2a-K661A. Conversely, KDM1A+2a(-/-) hESCs give rise to functional cardiac cells, displaying increased beating amplitude and frequency and enhanced expression of critical cardiogenic markers. Our findings prove the existence of a divergent scaffolding role of KDM1A splice variants, independent of their enzymatic activity, during hESC differentiation into cardiac cells

Association of COVID-19 Vaccinations With Intensive Care Unit Admissions and Outcome of Critically Ill Patients With COVID-19 Pneumonia in Lombardy, Italy

IMPORTANCE Data on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2-related pneumonia are scarce. OBJECTIVE To evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021. EXPOSURES COVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine). MAIN OUTCOMES AND MEASURES The incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders. RESULTS Among the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] agewas 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dosewas 0.03 (95% CI, 0.03-0.04; P <.001), whereas IRR of individuals who received an adenoviral vector vaccine after 120 days was 0.21 (95% CI, 0.19-0.24; P <.001). There were 553 patients admitted to an ICU for COVID-19 pneumonia during the study period: 139 patients (25.1%) were vaccinated and 414 (74.9%) were unvaccinated. Compared with unvaccinated patients, vaccinated patients were older (median [IQR]: 72 [66-76] vs 60 [51-69] years; P <.001), primarily male individuals (110 patients [ 79.1%] vs 252 patients [60.9%]; P <.001), with more comorbidities (median [IQR]: 2 [1-3] vs 0 [0-1] comorbidities; P <.001) and had higher ratio of arterial partial pressure of oxygen (PaO2) and fraction of inspiratory oxygen (FiO(2)) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P =.007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower PaO2/FiO(2) at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients. CONCLUSIONS AND RELEVANCE In this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status.These findings suggest a substantial reduction of the risk of developing COVID-19-related severe acute respiratory failure requiring ICU admission among vaccinated people

Exploring Cosmic Origins with CORE: Cosmological Parameters

We forecast the main cosmological parameter constraints achievable with theCORE space mission which is dedicated to mapping the polarisation of the CosmicMicrowave Background (CMB). CORE was recently submitted in response to ESA'sfifth call for medium-sized mission proposals (M5). Here we report the resultsfrom our pre-submission study of the impact of various instrumental options, inparticular the telescope size and sensitivity level, and review the great,transformative potential of the mission as proposed. Specifically, we assessthe impact on a broad range of fundamental parameters of our Universe as afunction of the expected CMB characteristics, with other papers in the seriesfocusing on controlling astrophysical and instrumental residual systematics. Inthis paper, we assume that only a few central CORE frequency channels areusable for our purpose, all others being devoted to the cleaning ofastrophysical contaminants. On the theoretical side, we assume LCDM as ourgeneral framework and quantify the improvement provided by CORE over thecurrent constraints from the Planck 2015 release. We also study the jointsensitivity of CORE and of future Baryon Acoustic Oscillation and Large ScaleStructure experiments like DESI and Euclid. Specific constraints on the physicsof inflation are presented in another paper of the series. In addition to thesix parameters of the base LCDM, which describe the matter content of aspatially flat universe with adiabatic and scalar primordial fluctuations frominflation, we derive the precision achievable on parameters like thosedescribing curvature, neutrino physics, extra light relics, primordial heliumabundance, dark matter annihilation, recombination physics, variation offundamental constants, dark energy, modified gravity, reionization and cosmicbirefringence. (ABRIDGED

Exploring cosmic origins with CORE: Cosmological parameters

We forecast the main cosmological parameter constraints achievable with the CORE space mission which is dedicated to mapping the polarisation of the Cosmic Microwave Background (CMB). CORE was recently submitted in response to ESA’s fifth call for mediumsized mission proposals (M5). Here we report the results from our pre-submission study of the impact of various instrumental options, in particular the telescope size and sensitivity level, and review the great, transformative potential of the mission as proposed. Specifically, we assess the impact on a broad range of fundamental parameters of our Universe as a function of the expected CMB characteristics, with other papers in the series focusing on controlling astrophysical and instrumental residual systematics. In this paper, we assume that only a few central CORE frequency channels are usable for our purpose, all others being devoted to the cleaning of astrophysical contaminants. On the theoretical side, we assume ΛCDM as our general framework and quantify the improvement provided by CORE over the current constraints from the Planck 2015 release. We also study the joint sensitivity of CORE and of future Baryon Acoustic Oscillation and Large Scale Structure experiments like DESI and Euclid. Specific constraints on the physics of inflation are presented in another paper of the series. In addition to the six parameters of the base ΛCDM, which describe the matter content of a spatially flat universe with adiabatic and scalar primordial fluctuations from inflation, we derive the precision achievable on parameters like those describing curvature, neutrino physics, extra light relics, primordial helium abundance, dark matter annihilation, recombination physics, variation of fundamental constants, dark energy, modified gravity, reionization and cosmic birefringence. In addition to assessing the improvement on the precision of individual parameters, we also forecast the post-CORE overall reduction of the allowed parameter space with figures of merit for various models increasing by as much as ∼ 107 as compared to Planck 2015, and 105 with respect to Planck 2015 + future BAO measurements

AN INTEGRATED FRAMEWORK FOR DOCUMENT MANAGEMENT: THE ROLE OF SEMANTIC AND ADMINISTRATIVE COOPERATION ABSTRACT

Nowadays, document management is one of the most important chalenges facing Public Administration‟s operators owing to the wide numbers of the PA information in form of documents such as agreements, forms, letters, contracts, deliberation, contracts, and so on. Moreover, most of the PA‟s business processes are based on document flows. In this context, the Information and Communication Technology (ICT) can plan again inter-organizational relationships inter and intra PA to (a) improve digital flows, and (b) share digital information to make a good use of information systems. We present a general framework for intelligent document management – DODIBOX-. It allows good productivity and major performance increases by applying intelligent technology to documents and document processing. The framework is organized by two different subsystems considering the design time and the run time functionalities. We explain the use of the framework together with richer representation of PA documents

Comparison of multiple definitions for Ventilator-Associated Pneumonia in patients requiring mechanical ventilation for non-pulmonary conditions: preliminary data from PULMIVAP, an Italian multicentre cohort study

Objectives: Compare intensivist-diagnosed VAP (iVAP) with four established definitions, assessing their agreement in detecting new episodes. Methods: Analysis from multicentric prospective study on pulmonary microbiota in patients requiring mechanical ventilation (MV). Data collected were used to compare hypothetical VAP onset according to iVAP with the study consensus criteria, the European Centre for Diseases Control and Prevention definition, and two versions of the latter adjusted for leukocyte count and fever. Results: In our cohort of 186 adult patients, iVAPs were 36.6% (68/186,95%CI=30.0%-44.0%), with an incidence rate of 4.64/100 patient-MVdays, and median MV-day at diagnosis of 6. Forty-seven percent of patients (87/186) were identified as VAP by at least one criterion, with a median MV-day at diagnosis of 5. Agreement between intensivist judgement (iVAP/no-iVAP) and the criteria was highest for the study consensus criteria (50/87, 57.4%), but still one-third of iVAP was not identified and 9% of patients were identified as VAP against intensivist diagnosis. VAP proportion differed among different criteria (25.2-30.1%). Conclusions: Caution is needed evaluating studies describing VAP incidence. Pre-agreed criteria and definitions that capture VAP's evolving nature provide greater consistency, but new clinically-driven definitions are needed to align surveillance and diagnostic criteria with clinical practice

Italian COnsensus in Neuroradiological Anesthesia (ICONA)

Anesthetic management of patients undergoing endovascular procedures for treating intracranial aneurysms or cerebrovascular malformations must consider a number of specific challenges, in addition to those associated with anesthesia for other specialties. In addition to maintenance of physiological stability, manipulation of systemic and cerebral hemodynamic parameters may be required to treat any sudden unexpected catastrophic neurological events. A multidisciplinary group including neuro- and pediatric anesthesiologists, interventional neuroradiologists, neurosurgeons, and a clinical methodologist contributed to this document. This consensus working group from 21 Italian institutions identified open questions regarding the best practices for management of anesthesia during endovascular neuroradiological procedures for intracranial aneurysms and cerebrovascular malformations, and addressed these by formulating practical consensus statements. At the first meeting in November 2015, nine key areas were identified regarding choice of anesthetic, patient monitoring, hemodynamic targets, postoperative care, and the management of neuromuscular blockade, anticoagulant and/or antiplatelet therapy, and special considerations for pediatric patients. Nine subgroups were established and a medical librarian performed literature searches in the Cochrane and MEDLINE/PubMed databases for each group. Groups drafted literature summaries and provisional responses in the form of candidate consensus statements based on evidence, when possible, and clinical experience, when this was lacking. Final wording was agreed at a meeting in April 2016 and where possible evidence was graded using United States Preventive Services Task Force criteria. Consensus (defined as >90% agreement) was based on evidence, clinical experience, clinician preference, feasibility in the Italian healthcare system, and cost/benefit considerations

Prone position in intubated, mechanically ventilated patients with COVID-19: a multi-centric study of more than 1000 patients

Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave. Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO2/FiO2 ratio increased 65 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position. Results: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p < 0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively). Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching