Effect of Early High-Dose Recombinant Human Erythropoietin on Behavior and Quality of Life in Children Aged 5 Years Born Very Preterm: Secondary Analysis of a Randomized Clinical Trial

IMPORTANCE In light of the promising neuroprotective properties of recombinant human erythropoietin (RHEpo), the Swiss EPO Neuroprotection Trial was started to investigate its effect on neurodevelopment in very preterm infants. The results of the primary and secondary outcome analysis did not show any effect of RHEpo on cognitive performance, neuromotor outcomes, or somatic growth of the study participants at ages 2 or 5 years. OBJECTIVE To investigate whether early high-dose RHEpo improves behavioral outcomes and health-related quality of life (HRQoL) at age 5 years. DESIGN, SETTING, AND PARTICIPANTS This was a prespecified secondary analysis of the double-blind, placebo-controlled, multicenter Swiss EPO Neuroprotection randomized clinical trial, which was conducted at 5 level-III perinatal centers in Switzerland. Infants born between 26 weeks 0 days' and 31 weeks 6 days' gestation were recruited between 2005 and 2012 and followed-up until age 5 years (last follow-up in 2018). Data were analyzed from January 6 to December 31, 2021. INTERVENTIONS Infants were assigned to receive either RHEpo (3000 IU/kg) or placebo (saline, 0.9%) intravenously 3 times within the first 42 hours after birth. MAIN OUTCOMES AND MEASURES The prespecified parent-reported measures of behavioral outcomes and health-related quality of life (HRQoL) of their children at the age of 5 years were assessed by two standardized questionnaires: the Strengths and Difficulties Questionnaire (behavioral outcomes) and the KIDSCREEN-27 (HRQoL). RESULTS Among 448 randomized infants, 228 infants were assigned to the RHEpo group and 220 infants were assigned to the placebo group. Questionnaire data were available for 317 children (71%) at a mean (SD) age of 5.8 (0.4) years (mean [SD] gestational age at birth, 29.3 [1.6] weeks; mean [SD] birth weight 1220 [340] grams; 128 [40%] female infants). At the age 5 years follow-up, the mean (SD) total difficulties score in the RHEpo group (8.41 [5.60] points) was similar to that of the placebo group (7.76 [4.81]) (P = .37). There were no statistically significant differences between the groups in any other outcome measures. CONCLUSIONS AND RELEVANCE This secondary analysis of a randomized clinical trial showed no evidence for an effect of early high-dose RHEpo administration on behavioral outcomes or HRQoL in children born very preterm at early school age. TRIAL REGISTRATION - ClinicalTrials.gov Identifier: NCT00413946

Energy gap and proximity effect in MgB2MgB_2 superconducting wires

Measurements of the penetration depth $\lambda (T,H)$ in the presence of a DC magnetic field were performed in $MgB_2$ wires. In as-prepared wires $\lambda (T,H<130 Oe)$ shows a strong diamagnetic downturn below $\approx 10 K$. A DC magnetic field of $130 Oe$ completely suppressed the downturn. The data are consistent with proximity coupling to a surface $Mg$ layer left during synthesis. A theory for the proximity effect in the clean limit, together with an assumed distribution of the $Mg$ layer thickness, qualitatively explains the field and temperature dependence of the data. Removal of the $Mg$ by chemical etching results in an exponential temperature dependence for $\lambda (T)$ with an energy gap of $2 \Delta (0)/T_c\approx 1.54$ ($\Delta(0) \approx 2.61 meV$), in close agreement with recent measurements on commercial powders and single crystals. This minimum gap is only 44% of the BCS weak coupling value, implying substantial anisotropy.Comment: RevTeX 4, 4 EPS figure

Shot Noise in Mesoscopic Diffusive Andreev Wires

We study shot noise in mesoscopic diffusive wires between a normal and a superconducting terminal. We particularly focus on the regime, in which the proximity-induced reentrance effect is important. We will examine the difference between a simple Boltzmann-Langevin description, which neglects induced correlations beyond the simple conductivity correction, and a full quantum calculation. In the latter approach, it turns out that two Andreev pairs propagating coherently into the normal metal are anti-correlated for E<E_c, where E_c=D/L^2 is the Thouless energy. In a fork geometry the flux-sensitive suppression of the effective charge was confirmed experimentally.Comment: 12 pages, proceedings of the NATO ARW MQO, Bled, Sloveni

Functional characterization of a 28-Kilobase Catabolic Island from Pseudomonas sp. Strain M1 involved in biotransformation of β-Myrcene and related plant-derived volatiles

Pseudomonas sp. strain M1 is able to mineralize highly hydrophobic and recalcitrant compounds, such as benzene, phenol, and their methylated/halogenated derivatives, as well as the backbone of several monoterpenes. The ability to use such a spectrum of compounds as the sole carbon source is, most probably, associated with a genetic background evolved under different environmental constraints. The outstanding performance of strain M1 regarding β-myrcene catabolism was elucidated in this work, with a focus on the biocatalytical potential of the β-myrcene-associated core code, comprised in a 28-kb genomic island (GI), predicted to be organized in 8 transcriptional units. Functional characterization of this locus with promoter probes and analytical approaches validated the genetic organization predictedin silicoand associated the β-myrcene-induced promoter activity to the production of β-myrcene derivatives. Notably, by using a whole-genome mutagenesis strategy, different genotypes of the 28-kb GI were generated, resulting in the identification of a novel putative β-myrcene hydroxylase, responsible for the initial oxidation of β-myrcene into myrcen-8-ol, and a sensor-like regulatory protein, whose inactivation abolished themyr + trait of M1 cells. Moreover, it was demonstrated that the range of monoterpene substrates of the M1 enzymatic repertoire, besides β-myrcene, also includes other acyclic (e.g., β-linalool) and cyclic [e.g.,R-(+)-limonene and (-)-β-pinene] molecules. Our findings are the cornerstone for following metabolic engineering approaches and hint at a major role of the 28-kb GI in the biotransformation of a broad monoterpene backbone spectrum for its future biotechnological applications.IMPORTANCEInformation regarding microbial systems able to biotransform monoterpenes, especially β-myrcene, is limited and focused mainly on nonsystematic metabolite identification. Complete and detailed knowledge at the genetic, protein, metabolite, and regulatory levels is essential in order to set a model organism or a catabolic system as a biotechnology tool. Moreover, molecular characterization of reported systems is scarce, almost nonexistent, limiting advances in the development of optimized cell factories with strategies based on the new generation of metabolic engineering platforms. This study provides new insights into the intricate molecular functionalities associated with β-myrcene catabolism inPseudomonas, envisaging the production of a molecular knowledge base about the underlying catalytic and regulatory mechanisms of plant-derived volatile catabolic pathways.Vectors from the Standard European Vector Architecture (SEVA) library and pBAM1 used in this work were kindly provided by Victor de Lorenzo (CNB-CSIC, Madrid, Spain). This work was supported by the strategic program UID/BIA/04050/2013 (POCI-01- 0145-FEDER-007569) funded by national funds through the FCT I.P. and by the ERDF through the COMPETE2020-Programa Operacional Competitividade e Internacionalização (POCI) and through a Ph.D. grant (grant SFRH/BD/76894/2011) to P.S.-C.info:eu-repo/semantics/publishedVersio

Metropolis simulations of Met-Enkephalin with solvent-accessible area parameterizations

We investigate the solvent-accessible area method by means of Metropolis simulations of the brain peptide Met-Enkephalin at 300$K$. For the energy function ECEPP/2 nine atomic solvation parameter (ASP) sets are studied. The simulations are compared with one another, with simulations with a distance dependent electrostatic permittivity $\epsilon (r)$, and with vacuum simulations ($\epsilon =2$). Parallel tempering and the biased Metropolis techniques RM$_1$ are employed and their performance is evaluated. The measured observables include energy and dihedral probability densities (pds), integrated autocorrelation times, and acceptance rates. Two of the ASP sets turn out to be unsuitable for these simulations. For all other systems selected configurations are minimized in search of the global energy minima, which are found for the vacuum and the $\epsilon(r)$ system, but for none of the ASP models. Other observables show a remarkable dependence on the ASPs. In particular, we find three ASP sets for which the autocorrelations at 300$$K are considerably smaller than for vacuum simulations.Comment: 10 pages and 8 figure

Potential functions of LEA proteins from the brine shrimp Artemia franciscana - Anhydrobiosis meets bioinformatics.

Late embryogenesis abundant (LEA) proteins are a large group of anhydrobiosis-associated intrinsically disordered proteins (IDP), which are commonly found in plants and some animals. The brine shrimp Artemiafranciscana is the only known animal that expresses LEA proteins from three, and not only one, different groups in its anhydrobiotic life stage. The reason for the higher complexity in the A. franciscana LEA proteome (LEAome), compared with other anhydrobiotic animals, remains mostly unknown. To address this issue, we have employed a suite of bioinformatics tools to evaluate the disorder status of the ArtemiaLEAome and to analyze the roles of intrinsic disorder in functioning of brine shrimp LEA proteins. We show here that A. franciscanaLEA proteins from different groups are more similar to each other than one originally expected, while functional differences among members of group 3 are possibly larger than commonly anticipated. Our data show that although these proteins are characterized by a large variety of forms and possible functions, as a general strategy, A. franciscana utilizes glassy matrix forming LEAs concurrently with proteins that more readily interact with binding partners. It is likely that the function(s) of both types, the matrix-forming and partner-binding LEA proteins, are regulated by changing water availability during desiccation

Quasiclassical theory of superconductivity: a multiple interface geometry

The purpose of the paper is to suggest a new method which allows one to study multiple coherent reflection/transmissions by partially transparent interfaces (e.g. in multi-layer mesoscopic structures or grain boundaries in high-Tc's) in the framework of the quasiclassical theory of superconductivity. It is argued that typically the trajectory of the particle is a simply connected tree (no loops) with knots, i.e. the points where interface scattering events occur and ballistic pieces of the trajectory are mixed. A linear boundary condition for the 2-component trajectory "wave function" which factorizes matrix (retarded) Green's function, is formulated for an arbitrary interface, specular or diffusive. To show the usage of the method, the current response to the vector potential (the total superfluid density rho_s) of a SS' sandwich with the different signs of the order parameter in S and S', is calculated. In this model, a few percent of reflection by the SS' interface transforms the paramagnetic response (rho_s < 0) created by the zero-energy Andreev bound states near an ideal interface (see Fauchere et al. PRL, 82, 3336 (1999), cond-mat/9901112), into the usual diamagnetic one (rho_s >0).Comment: Extended abstract submitted to "Electron Transport in Mesoscopic Systems", Satellite conference to LT22, Goteborg, 12-15 August, 1999. 2 pages Minor changes + the text height problem fixe

Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial

IMPORTANCE Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date. OBJECTIVE To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH. DESIGN, SETTING, AND PARTICIPANTS Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022. INTERVENTIONS Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life. MAIN OUTCOMES AND MEASURES Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023). RESULTS Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores. CONCLUSIONS AND RELEVANCE This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02076373

Energy dependent counting statistics in diffusive superconducting tunnel junctions

We present an investigation of the energy dependence of the full charge counting statistics in diffusive normal-insulating-normal-insulating-superconducting junctions. It is found that the current in general is transported via a correlated transfer of pairs of electrons. Only in the case of strongly asymmetric tunnel barriers or energies much larger than the Thouless energy is the pair transfer uncorrelated. The second cumulant, the noise, is found to depend strongly on the applied voltage and temperature. For a junction resistance dominated by the tunnel barrier to the normal reservoir, the differential shot noise shows a double peak feature at voltages of the order of the Thouless energy, a signature of an ensemble averaged electron-hole resonance.Comment: 8 pages, 5 figure