Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature

Introduction Since the frst description of gain of function (GOF) mutations in signal transducer and activator of transcrip tion (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefts in several reported cases, their indica tions, dosing, and monitoring remain to be established. Methods A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profle and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune defciency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p=0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions Our study supports the potentially benefcial use of JAKinibs in patients with STAT1 GOF, in line with previ ously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitor ing, as well as defning biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries

Tuning the electronic and magnetic properties of 2D g-GaN by H adsorption: An ab-initio study

We have theoretically studied the structural, electronic and magnetic properties of the hydrogen adsorption on a honeycomb gallium-nitride two-dimensional monolayer (2D g-GaN). Results indicate that the band gap energy can be systematically tuned by the hydrogen coverage on the 2D g-GaN in the diluted limit. In addition, a total magnetic moment can be induced in the 2D g-GaN by hydrogen adsorption due to s-p interaction and band structure effects. Although hydrogen adsorption on top of nitrogen atoms shows the most stable energy in the 2D g-GaN, the most stable ferromagnetism -with a nonzero magnetic moment-is obtained when hydrogen is adsorbed on top of Ga atoms. These results indicate that H adatoms on the 2D g-GaN systems could be a potential candidate for future spintronic applications

A proxy for carrying capacity of Mediterranean aquaculture

In developing a holistic and innovative approach to determining the carrying capacity in marine finfish aquaculture, we carried out a modified Delphi exercise in which we asked industry experts to identify the factors influencing the production levels of the activity under different scenarios. We disseminated and discussed three rounds of questionnaires in sectoral roundtables and workshops with experts, culminating in the development of a simple formula that adapts production levels to the physical, ecological, social and economic conditions of the activity on the Spanish Mediterranean coast. We used this formula to approach the carrying capacity of the system. Based on the developed model and its theoretical application, we estimated the carrying capacity for floating cages on the Spanish Mediterranean coast at 119,404 t—about 1.2 times the current production level of 96,440 t. We therefore concluded that, subject to the execution of an in-situ validation of the model, the production level of floating nurseries on the Spanish Mediterranean coast could be increased by up to 33.5%.KT-G was funded by a postdoctoral tenure program Juan de la Cierva Formación (FJCI-2014-20100) and Juan de la Cierva Incorporación (IJCI-2017-34174) funded by Spanish National Research Agency. This study was funded by the Projects “Environmental Innovation Measures for the Development and Establishment of Protocols for Carrying Capacity for Aquaculture Sustainability (MIMECCA)”; “Marine Aquaculture Carrying Capacity Applied Models (MACCAM)”; “GLObal change Resilience in Aquaculture-2 (GLORiA2),” supported by the Biodiversity Foundation of the Spanish Ministry for the Ecological Transition and Demographic Challenge, through the Pleamar Program and co-financed by the European Maritime and Fisheries Fund (EMFF). It is also part of the LIFE IP INTEMARES Project “Integrated, innovative and participatory management of the Natura 2000 Network in the Spanish marine environment”. This study forms part of the ThinkInAzul programme and was supported by MCIN with funding from European Union NextGenerationEU (PRTR-C17·I1) and by Generalitat Valenciana (THINKINAZUL/2021/044-TOWARDS)

An improved method for statistical studies of the internal kinematics of HII regions: the case of M 83

We present the integrated Halpha emission line profile for 157 HII regions in the central 3.4' x 3.4' of the galaxy M 83 (NGC 5236). Using the Fabry-Perot interferometer GHaFaS, on the 4.2 m William Herschel on La Palma, we show the importance of a good characterization of the instrumental response function for the study of line profile shapes. The luminosity-velocity dispersion relation is also studied, and in the log(L)-log(sigma) plane we do not find a linear relation, but an upper envelope with equation log(L)=0.9 *log(sigma)+38.1. For the adopted distance of 4.5 Mpc, the upper envelope appears at the luminosity L=10^38.5 ergs, in full agreement with previous studies of other galaxies, reinforcing the idea of using HII regions as standard candles.Comment: 13 pages, 9 figures, accepted for publication in MNRA

Diagnosis of cardiac surgery-associated acute kidney injury: State of the art and perspectives

Producción CientíficaDiagnosis of cardiac surgery-associated acute kidney injury (CSA-AKI), a syndrome of sudden renal dysfunction occurring in the immediate post-operative period, is still sub-optimal. Standard CSA-AKI diagnosis is performed according to the international criteria for AKI diagnosis, afflicted with insufficient sensitivity, specificity, and prognostic capacity. In this article, we describe the limitations of current diagnostic procedures and of the so-called injury biomarkers and analyze new strategies under development for a conceptually enhanced diagnosis of CSA-AKI. Specifically, early pathophysiological diagnosis and patient stratification based on the underlying mechanisms of disease are presented as ongoing developments. This new approach should be underpinned by process-specific biomarkers including, but not limited to, glomerular filtration rate (GFR) to other functions of renal excretion causing GFR-independent hydro-electrolytic and acid-based disorders. In addition, biomarker-based strategies for the assessment of AKI evolution and prognosis are also discussed. Finally, special focus is devoted to the novel concept of pre-emptive diagnosis of acquired risk of AKI, a premorbid condition of renal frailty providing interesting prophylactic opportunities to prevent disease through diagnosis-guided personalized patient handling. Indeed, a new strategy of risk assessment complementing the traditional scores based on the computing of risk factors is advanced. The new strategy pinpoints the assessment of the status of the primary mechanisms of renal function regulation on which the impact of risk factors converges, namely renal hemodynamics and tubular competence, to generate a composite and personalized estimation of individual risk.Instituto de Salud Carlos III y Fondo Europeo de Desarrollo Regional (FEDER) - (grant PI18/00996, PI21/01226), Unión Europea, Red de Investigación Renal (Enfermedad Renal) - (grant RICORS2040)Unión Europea–NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR) - (grant RD21/0005/0004)Junta de Castilla y León (Consejería de Educación) y Fondo Europeo de Desarrollo Regional (FEDER) - (grant IES160P20

Textural properties of synthetic nano-calcite produced by hydrothermal carbonation of calcium hydroxide

The hydrothermal carbonation of calcium hydroxide (Ca(OH)2) at high pressure of CO2 (initial PCO2 1/4 55 bar) and moderate to high temperature (30 and 90 1C) was used to synthesize fine particles of calcite. This method allows a high carbonation efficiency (about 95% of Ca(OH)2-CaCO3 conversion), a significant production rate (48 kg/m3 h) and high purity of product (about 96%). However, the various initial physicochemical conditions have a strong influence on the crystal size and surface area of the synthesized calcite crystals. The present study is focused on the estimation of the textural properties of synthesized calcite (morphology, specific surface area, average particle size, particle size distribution and particle size evolution with reaction time), using Rietveld refinements of X-ray diffraction (XRD) spectra, Brunauer-Emmett-Teller (BET) measurements, and scanning electron microscope (SEM) and transmission electron microscope (TEM) observations. This study demonstrate that the pressure, the temperature and the dissolved quantity of CO2 have a significant effect on the average particle size, specific surface area, initial rate of precipitation, and on the morphology of calcium carbonate crystals. In contrast, these PTx conditions used herein have an insignificant effect on the carbonation efficiency of Ca(OH)2. Finally, the results presented here demonstrate that nano-calcite crystals with high specific surface area (SBET 1/4 6-10m2/g) can be produced, with a high potential for industrial applications such as adsorbents and/or filler in papermaking industry

A micellar formulation of quercetin prevents cisplatin nephrotoxicity

Producción CientíficaThe antioxidant flavonoid quercetin has been shown to prevent nephrotoxicity in animal models and in a clinical study and is thus a very promising prophylactic candidate under development. Quercetin solubility is very low, which handicaps clinical application. The aim of this work was to study, in rats, the bioavailability and nephroprotective efficacy of a micellar formulation of Pluronic F127-encapsulated quercetin (P-quercetin), with improved hydrosolubility. Intraperitoneal administration of P-quercetin leads to an increased plasma concentration and bioavailability of quercetin compared to the equimolar administration of natural quercetin. Moreover, P-quercetin retains overall nephroprotective properties, and even slightly improves some renal function parameters, when compared to natural quercetin. Specifically, P-quercetin reduced the increment in plasma creatinine (from 3.4 ± 0.5 to 1.2 ± 0.3 mg/dL) and urea (from 490.9 ± 43.8 to 184.1 ± 50.1 mg/dL) and the decrease in creatinine clearance (from 0.08 ± 0.02 to 0.58 ± 0.19 mL/min) induced by the nephrotoxic chemotherapeutic drug cisplatin, and it ameliorated histological evidence of tubular damage. This new formulation with enhanced kinetic and biopharmaceutical properties will allow for further exploration of quercetin as a candidate nephroprotector at lower dosages and by administration routes oriented towards its clinical use.Fundación de Universidades y Enseñanzas Superiores de Castilla y León (FUESCyL) y Banco de Santander - (grant: Ed. 2014– 2015 Desafío UNIV-EMP)Fundación General de la Universidad de Salamanca, Fondo Europeo de Desarrollo Regional (FEDER) y Junta de Castilla y León - (grant: Ed. 2015 Lanzadera TC)Junta de Castilla y León - (grant: VA225U14

High-Flow Oxygen with Capping or Suctioning for Tracheostomy Decannulation

9 p.BACKGROUND When patients with a tracheostomy tube reach a stage in their care at which decannulation appears to be possible, it is common practice to cap the tracheostomy tube for 24 hours to see whether they can breathe on their own. Whether this approach to establishing patient readiness for decannulation leads to better outcomes than one based on the frequency of airway suctioning is unclear. METHODS In five intensive care units (ICUs), we enrolled conscious, critically ill adults who had a tracheostomy tube; patients were eligible after weaning from mechanical ventilation. In this unblinded trial, patients were randomly assigned either to undergo a 24-hour capping trial plus intermittent high-flow oxygen therapy (control group) or to receive continuous high-flow oxygen therapy with frequency of suctioning being the indicator of readiness for decannulation (intervention group). The primary outcome was the time to decannulation, compared by means of the log-rank test. Secondary outcomes included decannulation failure, weaning failure, respiratory infections, sepsis, multiorgan failure, durations of stay in the ICU and hospital, and deaths in the ICU and hospital. RESULTS The trial included 330 patients; the mean (±SD) age of the patients was 58.3±15.1 years, and 68.2% of the patients were men. A total of 161 patients were assigned to the control group and 169 to the intervention group. The time to decannulation was shorter in the intervention group than in the control group (median, 6 days [interquartile range, 5 to 7] vs. 13 days [interquartile range, 11 to 14]; absolute difference, 7 days [95% confidence interval, 5 to 9]). The incidence of pneumonia and tracheobronchitis was lower, and the duration of stay in the hospital shorter, in the intervention group than in the control group. Other secondary outcomes were similar in the two groups. CONCLUSIONS Basing the decision to decannulate on suctioning frequency plus continuous highflow oxygen therapy rather than on 24-hour capping trials plus intermittent highflow oxygen therapy reduced the time to decannulation, with no evidence of a between-group difference in the incidence of decannulation failure. (REDECAP ClinicalTrials.gov number, NCT02512744.

Optimizing dialysis dose in the context of frailty: an exploratory study

Introduction Frailty is a multicausal syndrome characterized by a decrease in strength, resistance and physiological function, which makes the individual vulnerable and dependent, and increases his/her mortality. This syndrome is more prevalent among older individuals, and chronic kidney disease patients, particularly those on dialysis. Dialysis dose is currently standardized for hemodialysis (HD) patients regardless of their age and functional status. However, it has been postulated that the dialysis dose required in older patients, especially frail ones, should be lower, since it could increase their degree of frailty. Then, the purpose of this study was to evaluate if there would be a correlation between the dose of Kt/V and the degree of frailty in a population of adult patients on HD. Materials and methods A cross-sectional study with 82 patients on HD in Barranquilla (Colombia) and Lobos (Argentina) was conducted. Socio-demographic and laboratory data, as well as dialysis doses (Kt/V) were recorded and scales of fragility, physical activity, gait and grip strength were applied. Then these data were correlated by a Spearman’s correlation and a logistic regression. Results CFS, social isolation, physical activity, gait speed, and prehensile strength tests were outside the reference ranges in the studied group. No significant correlation was found between dialysis dose and all the above mentioned functional tests. However, a significant and inverse correlation between physical activity and CFS was documented (score − 1.41 (CI − 2.1 to − 0.7). Conclusion No significant correlation was documented between Kt/V value and different parameters of the frailty status, but this status correlated significantly and inversely with physical activity in this group. Frailty status in hemodialysis patients was significantly higher in older individuals, although young individuals were not exempt from it