Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If ...left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.
Accurate snow depth observations are critical to assess water resources. More than a billion people rely on water from snow, most of which originates in the Northern Hemisphere mountain ranges. Yet, ...remote sensing observations of mountain snow depth are still lacking at the large scale. Here, we show the ability of Sentinel-1 to map the snow depth in the Northern Hemisphere mountains at 1 km² resolution using an empirical change detection approach. An evaluation with measurements from ~4,000 sites and reanalysis data demonstrates that the Sentinel-1 retrievals capture the spatial variability between and within mountain ranges, as well as their inter-annual differences. This is showcased with the contrasting snow depths between 2017 and 2018 in the US Sierra Nevada and European Alps. With Sentinel-1 continuity ensured until 2030 and likely beyond, these findings lay a foundation for quantifying the long-term vulnerability of mountain snow-water resources to climate change.
Low plasma CsA concentrations (<300-350 ng/mL) early following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of developing acute graft-versus-host ...disease (aGvHD). Nevertheless, the current optimal target trough concentration for CsA following HSCT is considered to be 200-400 ng/mL. Here, we performed a retrospective analysis of a homogeneous group of 129 patients who received HSCT after non-myeloablative conditioning, and we analyzed the impact of CsA trough concentration measured during the first four weeks (CsA W1-4) on the incidence aGvHD, relapse-free survival (RFS), non-relapse mortality (NRM), overall survival (OS), and toxicity. The 180-day incidence of grade II-IV aGvHD was 25% (32/129 patients). In multivariate analysis the incidence of grade II-IV aGvHD was significantly lower among patients with a CsA W1-4 concentration ≥350 ng/mL compared to patients with a concentration <350 ng/mL (18% versus 38%, respectively; P = 0.007), with a hazard ration (HR) of 0.38 (95% CI: 0.19-0.77). In contrast, we found no correlation between CsA trough concentration and RFS, NRM, or OS. Moreover, we found an increased incidence of hypomagnesemia at higher CsA concentrations, but no difference in the incidence of acute renal toxicity, hepatic toxicity, or electrolyte imbalance. Interestingly, 30% of patients experienced hyponatremia with no apparent cause other than the use of CsA, with urinalysis suggesting SIADH as the underlying cause. Our findings suggest that a CsA trough concentration of 350-500 ng/mL might be more appropriate in the first month following non-myeloablative HSCT.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations ...typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.
Starch is the main source of energy in commonly used pig diets. Besides effects related to the extent of starch digestion, also several effects related to variation in digestion rate have recently ...been demonstrated in non-ruminants. Different rates of starch digestion in animals and in in vitro models have been reported, depending on the botanic origin of starch. Starches from different botanic sources differ widely in structural and molecular properties. Predicting the effect of starch properties on in vitro digestion kinetics based on existing literature is hampered by incomplete characterization of the starches, or by a selective choice of starches from a limited number of botanic sources. This research aimed to analyse the relationships between starch properties and in vitro digestion kinetics of pure starches isolated from a broad range of botanic origins, which are used in non-ruminant diets or have a potential to be used in the future. Therefore we studied starch digestion kinetics of potato, pea, corn, rice, barley, and wheat starches, and analysed the granule diameter, number of pores, type and amount of crystalline structure, amylose content and amylopectin side-chain length of all starches.
Multivariate analysis revealed strong correlations among starch properties, leading us to conclude that effects of most starch characteristics are strongly interrelated. Across all analysed botanic sources, crystalline type and amylopectin chain length showed the strongest correlation with in vitro digestion kinetics. Increased percentages of A-type crystalline structure and amylopectin side chains of DP 6-24 both increased the rate of digestion. In addition, within, but not across, (clusters of) botanic sources, a decrease in amylose content and increase in number of pores correlated positively with digestion kinetics.
The type of crystalline structure and amylopectin chain length distribution of starch correlate significantly with digestion kinetics of starches across botanic sources in an in vitro pig model. Variation in digestion kinetics across botanic sources is not additively explained by other starch properties measured, but appears to be confined within botanical sources.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides ...is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.
ABSTRACT We present high-resolution (0 16) 870 m Atacama Large Millimeter/submillimeter Array (ALMA) imaging of 16 luminous ( ) submillimeter galaxies (SMGs) from the ALESS survey of the Extended ...Chandra Deep Field South. This dust imaging traces the dust-obscured star formation in these galaxies on ∼1.3 kpc scales. The emission has a median effective radius of Re = 0 24 0 02, corresponding to a typical physical size of 1.8 0.2 kpc. We derive a median Sérsic index of n = 0.9 0.2, implying that the dust emission is remarkably disk-like at the current resolution and sensitivity. We use different weighting schemes with the visibilities to search for clumps on 0 12 (∼1.0 kpc) scales, but we find no significant evidence for clumping in the majority of cases. Indeed, we demonstrate using simulations that the observed morphologies are generally consistent with smooth exponential disks, suggesting that caution should be exercised when identifying candidate clumps in even moderate signal-to-noise ratio interferometric data. We compare our maps to comparable-resolution Hubble Space Telescope -band images, finding that the stellar morphologies appear significantly more extended and disturbed, and suggesting that major mergers may be responsible for driving the formation of the compact dust disks we observe. The stark contrast between the obscured and unobscured morphologies may also have implications for SED fitting routines that assume the dust is co-located with the optical/near-IR continuum emission. Finally, we discuss the potential of the current bursts of star formation to transform the observed galaxy sizes and light profiles, showing that the descendants of these SMGs are expected to have stellar masses, effective radii, and gas surface densities consistent with the most compact massive ( 1-2 × 1011 ) early-type galaxies observed locally.
We present subkiloparsec-scale mapping of the 870 m ALMA continuum emission in six luminous (LIR ∼ 5 × 1012 L ) submillimeter galaxies (SMGs) from the ALESS survey of the Extended Chandra Deep Field ...South. Our high-fidelity 0 07-resolution imaging (∼500 pc) reveals robust evidence for structures with deconvolved sizes of 0.5-1 kpc embedded within (dominant) exponential dust disks. The large-scale morphologies of the structures within some of the galaxies show clear curvature and/or clump-like structures bracketing elongated nuclear emission, suggestive of bars, star-forming rings, and spiral arms. In this interpretation, the ratio of the "ring" and "bar" radii (1.9 0.3) agrees with that measured for such features in local galaxies. These potential spiral/ring/bar structures would be consistent with the idea of tidal disturbances, with their detailed properties implying flat inner rotation curves and Toomre-unstable disks (Q < 1). The inferred one-dimensional velocity dispersions ( r 70-160 km s−1) are marginally consistent with the limits implied if the sizes of the largest structures are comparable to the Jeans length. We create maps of the star formation rate density ( SFR) on ∼500 pc scales and show that the SMGs are able to sustain a given (galaxy-averaged) SFR over much larger physical scales than local (ultra)luminous infrared galaxies. However, on 500 pc scales, they do not exceed the Eddington limit set by radiation pressure on dust. If confirmed by kinematics, the potential presence of nonaxisymmetric structures would provide a means for net angular momentum loss and efficient star formation, helping to explain the very high star formation rates measured in SMGs.
Electron spin is fundamental in electrical and optical properties of organic electronic devices. Despite recent interest in spin mixing and spin transport in organic semiconductors, the actual spin ...coherence times in these materials have remained elusive. Measurements of spin coherence provide impartial insight into spin relaxation mechanisms, which is significant in view of recent models of spin-dependent transport and recombination involving high levels of spin mixing. We demonstrate coherent manipulation of spins in an organic light-emitting diode (OLED), using nanosecond pulsed electrically detected electron spin resonance to drive singlet-triplet spin Rabi oscillations. By measuring the change in photovoltaic response due to spin-dependent recombination, we demonstrate spin control of electronic transport and thus directly observe spin coherence over 0.5 s. This surprisingly slow spin dephasing underlines that spin mixing is not responsible for magnetoresistance in OLEDs. The long coherence times and the spin manipulation demonstrated are crucially important for expanding the impact of organic spintronics.
Clear guidance for successive antidepressant pharmacological treatments for non-responders in major depression is not well established.
Based on the RAND/UCLA Appropriateness Method, the French ...Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of treatment-resistant depression. The expert guidelines combine scientific evidence and expert clinicians' opinions to produce recommendations for treatment-resistant depression. A written survey comprising 118 questions related to highly-detailed clinical presentations was completed on a risk-benefit scale ranging from 0 to 9 by 36 psychiatrist experts in the field of major depression and its treatments. Key-recommendations are provided by the scientific committee after data analysis and interpretation of the results of the survey.
The scope of these guidelines encompasses the assessment of pharmacological resistance and situations at risk of resistance, as well as the pharmacological and psychological strategies in major depression.
The expert consensus guidelines will contribute to facilitate treatment decisions for clinicians involved in the daily assessment and management of treatment-resistant depression across a number of common and complex clinical situations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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