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Objective: The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD).Methods: This systematic review and meta-analysis included searches of MEDLINE ALL, Embase, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of loss of ambulation in DMD. Search terms included “Duchenne muscular dystrophy” as a Medical Subject Heading or free text term, in combination with variations of the term “predictor”. Risk of bias was assessed using the Newcastle–Ottawa Scale. We performed meta-analysis pooling of hazard ratios of the effects of glucocorticoids (vs. no glucocorticoid therapy) by fitting a common-effect inverse-variance model.Results: The bibliographic searches resulted in the inclusion of 45 studies of children and adults with DMD from 17 countries across Europe, Asia, and North America. Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40–0.48]) (n?=?25 studies). Earlier onset of first signs or symptoms, earlier loss of developmental milestones, lower baseline 6MWT (i.e.,<350 vs. =350 metres and <330 vs. =330 metres), and lower baseline NSAA were associated with earlier loss of ambulation (n?=?5 studies). Deletion of exons 3–7, proximal mutations (upstream intron 44), single exon 45 deletions, and mutations amenable of skipping exon 8, exon 44, and exon 53, were associated with prolonged ambulation; distal mutations (intron 44 and downstream), deletion of exons 49–50, and mutations amenable of skipping exon 45, and exon 51 were associated with earlier loss of ambulation (n?=?13 studies). Specific single-nucleotide polymorphisms in CD40gene rs1883832, LTBP4gene rs10880, SPP1gene rs2835709 and rs11730582, and TCTEX1D1gene rs1060575 (n?=?7 studies), as well as race/ethnicity and level of family/patient deprivation (n?=?3 studies), were associated with loss of ambulation. Treatment with ataluren (n?=?2 studies) and eteplirsen (n?=?3 studies) were associated with prolonged ambulation. Magnetic resonance biomarkers (MRI and MRS) were identified as significant predictors of loss of ambulation (n?=?6 studies). In total, 33% of studies exhibited some risk of bias.Conclusion: Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population.

In this study, we use surface-sensitive vibrational sum-frequency generation (VSFG) spectroscopy to investigate the interaction between model lipid monolayers and Aβ(1–42) in its monomeric and aggregated states. Combining VSFG with atomic force microscopy (AFM) and thioflavin T (ThT) fluorescence measurements, we found that only small aggregates with probably a β-hairpin-like structure adsorbed to the zwitterionic lipid monolayer (DOPC). In contrast, larger aggregates with an extended β-sheet structure adsorbed to a negatively charged lipid monolayer (DOPG). The adsorption of small, initially formed aggregates strongly destabilized both monolayers, but only the DOPC monolayer was completely disrupted. We showed that the intensity of the amide-II′ band in achiral (SSP) and chiral (SPP) polarization combinations increased in time when Aβ(1–42) aggregates accumulated at the DOPG monolayer. Nevertheless, almost no adsorption of preformed mature fibrils to DOPG monolayers was detected. By performing spectral VSFG calculations, we revealed a clear correlation between the amide-II′ signal and the degree of amyloid aggregates (e.g., oligomers or (proto)fibrils) of various Aβ(1–42) structures. The calculations showed that only structures with a significant amyloid β-sheet content have a strong amide-II′ intensity, in line with previous Raman studies. The combination of the presented results substantiates the amide-II(′) band as a legitimate amyloid marker.

We use vibrational sum-frequency generation (VSFG) spectroscopy to study the structure of hen egg-white lysozyme (HEWL) aggregates adsorbed to DOPG/D2O and air/D2O interfaces. We find that aggregates with a parallel and antiparallel β-sheet structure together with smaller unordered aggregates and a denaturated protein are adsorbed to both interfaces. We demonstrate that to retrieve this information, fitting of the VSFG spectra is essential. The number of bands contributing to the VSFG spectrum might be misinterpreted, due to interference between peaks with opposite orientation and a nonresonant background. Our study identified hydrophobicity as the main driving force for adsorption to the air/D2O interface. Adsorption to the DOPG/D2O interface is also influenced by hydrophobic interaction; however, electrostatic interaction between the charged protein’s groups and the lipid’s headgroups has the most significant effect on the adsorption. We find that the intensity of the VSFG spectrum at the DOPG/D2O interface is strongly enhanced by varying the pH of the solution. We show that this change is not due to a change of lysozyme’s and its aggregates’ charge but due to dipole reorientation at the DOPG/D2O interface. This finding suggests that extra care must be taken when interpreting the VSFG spectrum of proteins adsorbed at the lipid/water interface.

Background: SMA affects individuals with a broad age range and spectrum of disease severity. Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral SMN2 pre-mRNA splicing modifier. Methods: SUNFISH is a multicenter, two-part, randomized, placebo-controlled, double-blind study in patients with Types 2/3 SMA. Part 1 assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam dose levels in patients with Types 2/3 SMA. Part 2 assessed the efficacy and safety of the selected dose of risdiplam versus placebo in Type 2 and non-ambulant Type 3 SMA. In Part 2, participants were treated with risdiplam or placebo for 12 months, then received risdiplam in a blinded manner until month 24. At month 24, patients were offered the opportunity to enter the open-label extension phase. Results: Change from baseline in MFM32 total score (Part 2- primary endpoint) in patients treated with risdiplam versus placebo was met at month 12. These increases in motor function were sustained in the second and third year after risdiplam treatment. Here we present 4-year efficacy and safety data from SUNFISH. Conclusions: SUNFISH is ongoing and will provide further long-term efficacy and safety data of risdiplam in a broad population of individuals with SMA.

We use surface-specific heterodyne-detected vibrational sum-frequency generation spectroscopy (HD-VSFG) and surface tension measurements to investigate the molecular structure of the surface of aqueous solutions of poly(vinyl alcohol) (PVA) polymers with average molecular weights of 10000 and 125000 g/mol. We find that the interfacial water molecules have a preferred orientation with their hydrogen-bonded O–H groups pointing away from the bulk, for both PVA10000and PVA125000. This observation is explained from the ongoing hydrolysis of the acetyl impurities on the PVA polymer chains. This hydrolysis yields negatively charged acetate ions that have a relatively high surface propensity. For both PVA10000and PVA125000the strong positive signal vanishes when the pH is decreased, due to the neutralization of the acetate ions. For solutions with a high concentration of PVA10000the interfacial water signal becomes very small, indicating that the surface gets completely covered with a disordered PVA polymer film. In contrast, for high concentrations of PVA125000, the strong positive water signal persists at high pH, which shows that the water surface does not get completely covered. The HD-VSFG data combined with surface tension data indicate that concentrated PVA125000solutions form a structured surface layer with pores containing a high density of interfacial water.

We applied the low energy (e,2e) spectroscopy in reflection-mode scattering geometry for studying ordered oxygen adsorption on W(001). Primary electrons with the energy of 36 eV were used to excite the correlated electron pairs from a p(2x1) adsorbed oxygen layer. The (e,2e) spectra of clean and oxygen covered W(001) surface were analyzed. It was found that the adsorption of 1 ML of oxygen on W(001) leads to the appearance of an additional structure in the energy distribution of correlated pairs. This structure corresponds to the excitation of electrons from the energy level located at 6.7 ± 0.5 eV below the Fermi level. This result is consistent with the UPS study of the oxygen adsorption on W(001) [1] where the adsorbate photoemission peak was obsewed at 6.5 eV below Fermi level. A theoretical analysis of the emission process is developed and used to explain the main structures in the observed electron pair spectra.

We present experimental evidence on photo double ionization processes in the valence band of solids. Applying a 'Time-of-Flight' electron spectroscopy technique, we measured the energy distribution of pairs of correlated electrons emitted from clean Cu(001)- and Ni(001)- crystals upon absorption of linearly polarized photons of 45eV energy. Data were taken for normal and grazing orientation of the light wave vector with respect to the crystal surfaces. The energy sharing distributions of electron pairs emitted from the vicinity of the Fermi-level show significant differences for Cu and Ni. For interpretation of our data, we consider a direct double ionization mechanism in competition with a two step process involving single photoexcitation and a subsequent collision of the photoelectron with an additional band electron. A theoretical approach by J. Berakdar including both mechanisms is in good agreement with our data. In this theory the differences between Cu and Ni are traced back to distinct relative contributions of both mechanisms in the two metals due to the different average electron density.

Abstract.:  The mode of reproduction, pollen production, chromosome numbers, genetic variation (RAPD, allozymes) and overall similarity were studied in 6 species of Hieracium sect. Alpina in the Tatry Mts. (the Western Carpathians, Slovakia). All species were confirmed to be agamospermous and, except of H. krivanense and H. slovacum, lacking pollen grains. For the first time, a chromosome number is reported for H. krivanense (2n=4x=36). Considerable genetic variation was revealed in H. alpinum and a correlation between geographic and genetic distances was found in this species. Between-population variation in RAPD and allozyme phenotypes was found in H. pinetophilum and H. crassipedipilum. In all other species, allozyme and RAPD variation was low or absent. With few exceptions, the species differ in their allozyme as well as RAPD patterns. The relatedness of one population of endemic H. slovacum and H. halleri was confirmed. It is shown, that Carpathian species of the H. fritzei group are derived from at least two ancestors.

We report on the structural and magnetic characterization of Ni/Fe/MgO/Fe structures grown on GaAs(001) and InP(001). High-resolution transmission electron microscopy images confirm a good crystallographic order of the structures grown on GaAs(001). On the contrary, the structures grown on InP(001) do not show any long-range crystallographic order. For structures grown on GaAs(001), magneto optic Kerr effect analysis shows steps in the hysteresis loops corresponding to magnetization reversal processes that occur independently in both ferromagnetic (FM) films. No FM coupling between the bottom Fe and the top Ni/Fe films is detected. The coercivity of the bottom Fe film in the junction is increased in comparison to the Fe/GaAs(001) film of the same thickness most likely due to crystallographic defects. The defects are created in the top Ni/Fe bilayer and are spread over the whole single-crystalline structure. For structures grown on InP(001), a strong FM coupling is deduced from the hysteresis loops and is interpreted in terms of the orange-peel coupling.

The article reviews recent measurements using the Magnetization induced Second Harmonic Generation (MSHG) from ultrathin metallic films and multilayers. Emphasis is put on the high surface and interface sensitivity and the influence of ‘quantum well states’ (QWS). With the example of a Ni/Cu/Ni/Cu(001) multilayer structure we show that there is a net (magnetic) contribution from the symmetrically buried lower Ni layer because of the presence of QWS in the Cu spacer layer, which makes the observation of antiferromagnetic coupling in the Ni/Cu/Ni/Cu(001) structure possible with MSHG.

Abstract: The secondary electron distributionN(E) obtained with a spherical grid retarding field analyser is stored in a multichannel analyser. The experimental intensities of Auger lines are accurately determined by numerically substracting the background in theN(E) distribution and taking the area under the resulting peaks. Broadening of the lines due to several experimental factors, the multiple structure of the lines and the characteristics energy losses are taken into account. The absolute atomic densities on the surface are deducted from the Auger line intensities by a simple theoretical model. A comparison is made with atomic densities on the surface which are known either from the crystal structure (cleaved muscovite) or from Rutherford backscattering experiments (thin layer of Ag) or simply from the specific weight in the case of bulk materials (C, Cu, Ag). The maximum deviation is smaller than a factor of 2. Generally, the values differ by about 30%, which shows that AES, performed in this way, can give reliable quantitative results for densities ranging from a fraction of a monolayer to the bulk material.

Abstract: A definition of edge resolution is proposed, which is adapted to the pecularities of scanning Auger microscopy. Based on recent monte-Carlo computer simulations for scanning electron microscopy, the influence of backscattered electrons on the edge resolution is estimated for low-Z (Al) and high-Z materials (Au). The resolution is found to be of the order of 100nm and to be nearly independent of the atomic number of the sample.

Herbarium specimens (c. 1 000) and population samples (76) have been screened for the occurrence of diploid representatives ofTaraxacum sect.Ruderalia (T. sect.Vulgaria, nom. illeg.). The area studied comprises German Democratic Republic, Poland, Czechoslovakia, Hungary and parts of Austria, Yugoslavia, and Rumania. Diploids are common from the Valley of the Moravia river on southwards. Isolated outpost localities are found in S. Poland and extend far to the north: neighbourhood of Berlin. Based on the pattern of distribution in Czechoslovakia, the Pannonian (thermophilous) phytogeographical character of the diploids is discussed. Special attention has been paid to morphological differences between di- and triploids in Czechoslovakia. The study provides a basis for further biosystematical and taxonomic studies in the relationships between diploids and polyploids as well as in the stability of agamospecies.

The use of spin-polarization analysis in electron spectroscopy of magnetic and non-magnetic surfaces is demonstrated with a few examples. The existence and properties of spin-dependent transmission of electrons through the solid-vacuum interface is shown. The influence of surface reconstruction of Pt(110) on spin polarization and energy distribution curves in photoemission with circularly polarized light is studied. The polarization of secondary electrons from Fe(110) is observed to depend on the spin polarization of primary electrons at low energies. The temperature dependence of the exchange splitting in Ni is studied by means of spin-polarized electron energy loss spectroscopy and found to be at variance with the assumptions of the Stoner-Wohlfarth theory.

Polarized photoelectrons from NEA GaAs0.6P0.4 are for the first time analysed simultaneously with respect to spin and energy. Parameters of photon energy and temperature were chosen suitable for a polarized electron source cathode. Various contributions to the intensity- and polarization-distribution in connection with several depolarization mechanisms are discussed. Electron-hole exchange scattering together with multiple reflections in the space charge region qualitatively explain the observed distributions. Consequences for a polarized electron source are pointed out.

The fluence dependence of the sputtering yield has been studied on amorphous silicon under uhv conditions with 0.5 to 5keV Ar+ using the KARMA technique (Kombinierte Auger/Röntgen Mikro-Analyse). It allows to measure simultaneously the surface composition, the differential sputtering yield, and the total amount of implanted gas. For all energies, the yield increases initially and reaches saturation after the removal of a layer the thickness of which is closely correlated to the ion range. Gas implantation as a cause for these fluence effects can be ruled out by quantitative analysis. The relative yield increase is found to be larger for low energies than for higher ones. Both these findings can be qualitatively explained by a simple damage collection model.

Abstract: We describe a simple particle detector using the principle of the ion-electron converter. It detects ions and neutral particles, has low background noise (0.1 counts/s), and is bakeable at 280C. The energy resolution of the electron detector is better than 2.0 keV, thus allowing the frequency distribution of the electron groups to be observed directly in the pulse height spectrum. The marked differences between the electron statistics for ions and for metastable neutrals are used in an application to mass-analysis. An improvement in signal to noise ratio by more than a factor of ten is achieved.

Spin-polarized photoemission with circularly polarized light represents a relatively new technique in surface science. It became feasible with the increased availability of circularly polarized light in the vacuum ultraviolet and soft X-ray regime, generated in dedicated synchrotron radiation facilities. Another important ingredient was the development of efficient electron spin polarization detectors. Supported by group theoretical considerations, this technique was first employed to study the process of optical spin orientation in single crystalline non-magnetic materials. In these samples, spin-dependent effects arise solely from spin-orbit coupling. The experiments revealed the strong influence of spin-orbit coupling on the details of the electronic band structure, such as the symmetry character of the electronic wave functions, hybridization phenomena, and the behavior of degeneracies. The results opened the way to a detailed understanding of the electronic structure and permit a rigorous test of both state-of-the-art bulk band theories and fully relativistic photoemission calculations. Since 1990, spin-polarized photoemission with circularly polarized light is also used to investigate ferromagnetic systems. These experiments led to the discovery of the counterpart of optical spin orientation in ferromagnets, namely, the magnetic dichroisms. Magnetic dichroism means that the spin-dependent photoexcitation from a ferromagnetically ordered system manifests itself already in the photoelectron intensity distributions. Because of this particular property, techniques based on magnetic dichroisms are currently receiving wide interest in the spectroscopic investigation of magnetic systems and phenomena.The following article reviews the current status of the field of spin- and angle-resolved photoemission from solids using circularly polarized radiation. We survey the development of this technique over the last 10 years, covering its applications to both non-magnetic and ferromagnetic systems.