GNAO1 encephalopathy : further delineation of a severe neurodevelopmental syndrome affecting females

De novo heterozygous mutations in the GNAO1 gene, encoding the Gα o subunit of G-proteins, are the cause of a severe neurodevelopmental disorder, featuring early infantile seizures, profound cognitive dysfunction and, occasionally, movement disorder (early infantile epileptic encephalopathy-17). We report a further case of this association in a 20 month-old Spanish girl with neonatal-onset refractory seizures, progressive microcephaly, oral-lingual dyskinesia and nearly absent psychomotor development. We performed whole-exome sequencing, a computational structural analysis of the novel gene variant identified and reviewed the previously reported cases. Trio whole-exome-sequencing uncovered a de novo p.Leu199Pro GNAO1 mutation. Computational structural analysis indicates this novel variant adversely affects the stability of the G-protein heterotrimeric complex as a whole. Of note, our patient showed a sustained seizure reduction while on a ketogenic diet. With this observation, a total of twelve patients with GNAO1 encephalopathy have been reported. Oral-lingual dyskinesia and responsiveness of seizures to ketogenic diet are novel features. The distorted sex ratio (12/12 females) of the condition remains unexplained; a differential gender effect of the disruption of G-protein- mediated signal transduction on the developing brain can be hypothesized. The online version of this article (doi:10.1186/s13023-016-0416-0) contains supplementary material, which is available to authorized users

Radio survey of the stellar population in the infrared dark cloud G14.225-0.506

[Context] The infrared dark cloud (IRDC) G14.225-0.506 is part of the extended and massive molecular cloud located to the southwest of the H II region M17. The cloud is associated with a network of filaments, which result in two different dense hubs, as well as with several signposts of star formation activity and a rich population of protostars and young stellar objects (YSOs).[Aims] The aim of this work is to study the centimeter continuum emission in order to characterize the stellar population in both regions, as well as to study the evolutionary sequence across the IRDC G14.225-0.506.[Methods] We performed deep (~ 1.5–3 μJy) radio continuum observations at 6 and 3.6 cm toward the IRDC G14.225-0.506 using the Karl G. Jansky Very Large Array (VLA) in its most extended A configuration (~0.3″). Data at both C and X bands were imaged using the same (u,v) range in order to derive spectral indices. We have also made use of observations taken during different days to study the presence of variability at short timescales toward the detected sources.[Results] We detected a total of 66 sources, 32 in the northern region G14.2-N and 34 in the southern region G14.2-S. Ten of the sources are found to be variable, with three located in G14.2-N and seven in G14.2-S. Based on their spectral index, the emission in G14.2-N is mainly dominated by nonthermal sources while G14.2-S contains more thermal emitters. Approximately 75% of the sources present a counterpart at other wavelengths. When considering the inner 0.4 pc region around the center of each hub, the number of infrared (IR) sources in G14.2-N is larger than in G14.2-S by a factor of 4. We also studied the relation between the radio luminosity and the bolometric luminosity, finding that the thermal emission of the studied sources is compatible with thermal radio jets. For our sources with X-ray counterparts, the nonthermal emitters follow a Güdel-Benz relation with κ = 0.03, as previously suggested for other similar regions.[Conclusions] We found similar levels of fragmentation between G14.2-N and G14.2-S, suggesting that both regions are most likely twin hubs. The nonthermal emission found in the less evolved objects, mainly coming from G14.2-N, suggests that G14.2-N may be composed of more massive YSOs as well as being in a more advanced evolutionary stage, consistent with the “filament-halo” gradient in age and mass from previous works. Overall, our results confirm a wider evolutionary sequence from the southwest to northeast starting in G14.2-S as the youngest part, followed by G14.2-N, and ending with the most evolved region M17.Project supported by a 2022 Leonardo Grant for Researchers in Physics from the BBVA Foundation. The BBVA Foundation accepts no responsibility for the opinions, statements and contents included in the project and/or the results thereof, which are entirely the responsibility of the authors. E.D.D., G.B., J.M.G., A.S.M., and R.E. acknowledge support from the PID2020-117710GB-I00 grant funded by MCIN/ AEI /10.13039/501100011033. A.S.M. acknowledges support from the RyC2021-032892-I grant funded by MCIN/AEI/10.13039/501100011033 and by the European Union ‘Next GenerationEU’/PRTR, as well as the program Unidad de Excelencia María de Maeztu CEX2020-001058-M. A.P. acknowledges financial support from the UNAM-PAPIIT IG100223 grant, the Sistema Nacional de Investigadores of CONAHCyT, and from the CONAHCyT project number 86372 of the ‘Ciencia de Frontera 2019’ program, entitled ‘Citlalcóatl: A multi-scale study at the new frontier of the formation and early evolution of stars and planetary systems’, Mexico. N.A.L. acknowledges support from the European Research Council synergy grant ECOGAL (Grant : 855130). H.B.L. is supported by the National Science and Technology Council (NSTC) of Taiwan (Grant Nos. 111-2112-M-110-022-MY3).With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2020-001058-M).Peer reviewe

Parenteral Nutrition: Current Use, Complications, and Nutrition Delivery in Critically Ill Patients

Background: Parenteral nutrition (PN) is needed to avoid the development of malnutrition when enteral nutrition (EN) is not possible. Our main aim was to assess the current use, complications, and nutrition delivery associated with PN administration in adult critically ill patients, especially when used early and as the initial route. We also assessed the differences between patients who received only PN and those in whom EN was initiated after PN (PN-EN). Methods: A multicenter (n = 37) prospective observational study was performed. Patient clinical characteristics, outcomes, and nutrition-related variables were recorded. Statistical differences between subgroups were analyzed accordingly. Results: From the entire population (n = 629), 186 (29.6%) patients received PN as initial nutrition therapy. Of these, 74 patients (11.7%) also received EN during their ICU stay (i.e., PNEN subgroup). PN was administered early (<48 h) in the majority of patients (75.3%; n = 140) and the mean caloric (19.94 +/- 6.72 Kcal/kg/day) and protein (1.01 +/- 0.41 g/kg/day) delivery was similar to other contemporary studies. PN showed similar nutritional delivery when compared with the enteral route. No significant complications were associated with the use of PN. Thirty-two patients (43.3%) presented with EN-related complications in the PN-EN subgroup but received a higher mean protein delivery (0.95 +/- 0.43 vs 1.17 +/- 0.36 g/kg/day; p = 0.03) compared with PN alone. Once adjusted for confounding factors, patients who received PN alone had a lower mean protein intake (hazard ratio (HR): 0.29; 95% confidence interval (CI): 0.18-0.47; p = 0.001), shorter ICU stay (HR: 0.96; 95% CI: 0.91-0.99; p = 0.008), and fewer days on mechanical ventilation (HR: 0.85; 95% CI: 0.81-0.89; p = 0.001) compared with the PN-EN subgroup. Conclusion: The parenteral route may be safe, even when administered early, and may provide adequate nutrition delivery. Additional EN, when possible, may optimize protein requirements, especially in more severe patients who received initial PN and are expected to have longer ICU stays. NCT Registry: 03634943

Evaluation of Nutritional Practices in the Critical Care Patient (The ENPIC Study): Does Nutrition Really Affect ICU Mortality?

Background & aims: The importance of artificial nutritional therapy is underrecognized, typically being considered an adjunctive rather than a primary therapy. We aimed to evaluate the influence of nutritional therapy on mortality in critically ill patients. Methods: This multicenter prospective observational study included adult patients needing artificial nutritional therapy for >48 h if they stayed in one of 38 participating intensive care units for >= 72 h between April and July 2018. Demographic data, comorbidities, diagnoses, nutritional status and therapy (type and details for <= 14 days), and outcomes were registered in a database. Confounders such as disease severity, patient type (e.g., medical, surgical or trauma), and type and duration of nutritional therapy were also included in a multivariate analysis, and hazard ratios (HRs) and 95% confidence intervals (95% CIs) were reported. Results: We included 639 patients among whom 448 (70.1%) and 191 (29.9%) received enteral and parenteral nutrition, respectively. Mortality was 25.6%, with non-survivors having the following char-acteristics: older age; more comorbidities; higher Sequential Organ Failure Assessment (SOFA) scores (6.6 +/- 3.3 vs 8.4 +/- 3.7; P < 0.001); greater nutritional risk (Nutrition Risk in the Critically Ill [NUTRIC] score: 3.8 +/- 2.1 vs 5.2 +/- 1.7; P < 0.001); more vasopressor requirements (70.4% vs 83.5%; P=0.001); and more renal replacement therapy (12.2% vs 23.2%; P=0.001). Multivariate analysis showed that older age (HR: 1.023; 95% CI: 1.008-1.038; P=0.003), higher SOFA score (HR: 1.096; 95% CI: 1.036-1.160; P=0.001), higher NUTRIC score (HR: 1.136; 95% CI: 1.025-1.259; P=0.015), requiring parenteral nutrition after starting enteral nutrition (HR: 2.368; 95% CI: 1.168-4.798; P=0.017), and a higher mean Kcal/Kg/day intake (HR: 1.057; 95% CI: 1.015-1.101; P=0.008) were associated with mortality. By contrast, a higher mean protein intake protected against mortality (HR: 0.507; 95% CI: 0.263-0.977; P=0.042). Conclusions: Old age, higher organ failure scores, and greater nutritional risk appear to be associated with higher mortality. Patients who need parenteral nutrition after starting enteral nutrition may represent a high-risk subgroup for mortality due to illness severity and problems receiving appropriate nutritional therapy. Mean calorie and protein delivery also appeared to influence outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism

Beyond faith: Biomolecular evidence for changing urban economies in multi‐faith medieval Portugal

During the Middle Ages, Portugal witnessed unprecedented socioeconomic and religious changes under transitioning religious political rule. The implications of changing ruling powers for urban food systems and individual diets in medieval Portugal is poorly understood. This study aimed to elucidate the dietary impact of the Islamic and Christian conquests.info:eu-repo/semantics/publishedVersio

HE-LHC: The High-Energy Large Hadron Collider: Future Circular Collider Conceptual Design Report Volume 4

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1

We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics