Long-term teduglutide associated with improved response in pediatric short bowel syndrome-associated intestinal failure.

OBJECTIVES: Patients with short bowel syndrome-associated intestinal failure (SBS-IF) require long-term parenteral nutrition and/or intravenous fluids (PN/IV) to maintain fluid or nutritional balance. We report the long-term safety, efficacy, and predictors of response in pediatric patients with SBS-IF receiving teduglutide over 96 weeks. METHODS: This was a pooled, post hoc analysis of two open-label, long-term extension (LTE) studies (NCT02949362 and NCT02954458) in children with SBS-IF. Endpoints included treatment-emergent adverse events (TEAEs) and clinical response (≥20% reduction in PN/IV volume from baseline). A multivariable linear regression identified predictors of teduglutide response; the dependent variable was mean change in PN/IV volume at each visit over 96 weeks. RESULTS: Overall, 85 patients were analyzed; 78 patients received teduglutide in the parent and/or LTE studies (any teduglutide [TED] group), while seven patients did not receive teduglutide in either the parent or LTE studies. Most TEAEs were moderate or severe in intensity in both groups. By week 96, 82.1% of patients from the any TED group achieved a clinical response, with a mean fluid decrease of 30.1 mL/kg/day and an energy decrease of 21.6 kcal/kg/day. Colon-in-continuity, non-White race, older age at baseline, longer duration of teduglutide exposure, and increasing length of remaining small intestine were significantly associated with a reduction in mean PN/IV volume requirements. CONCLUSIONS: In pediatric patients with SBS-IF, teduglutide treatment resulted in long-term reductions in PN/IV requirements. The degree of PN/IV volume reduction depended on the duration of teduglutide exposure, underlying bowel anatomy, and demographics.

Resolving length-scale-dependent transient disorder through an ultrafast phase transition.

Material functionality can be strongly determined by structure extending only over nanoscale distances. The pair distribution function presents an opportunity for structural studies beyond idealized crystal models and to investigate structure over varying length scales. Applying this method with ultrafast time resolution has the potential to similarly disrupt the study of structural dynamics and phase transitions. Here we demonstrate such a measurement of CuIr2S4 optically pumped from its low-temperature Ir-dimerized phase. Dimers are optically suppressed without spatial correlation, generating a structure whose level of disorder strongly depends on the length scale. The redevelopment of structural ordering over tens of picoseconds is directly tracked over both space and time as a transient state is approached. This measurement demonstrates the crucial role of local structure and disorder in non-equilibrium processes as well as the feasibility of accessing this information with state-of-the-art XFEL facilities.

Teduglutide improves liver chemistries in short bowel syndrome-associated intestinal failure: Post hoc analysis.

BACKGROUND: Chronic hepatic complications are common in patients with short bowel syndrome-associated intestinal failure (SBS-IF). Teduglutide, a glucagon-like peptide-2 analogue, demonstrated efficacy in reducing parenteral nutrition and/or intravenous fluid dependence among patients with SBS-IF in phase 3 clinical studies. METHODS: This was a post hoc analysis of pooled data from two separate randomized, double-blind, placebo-controlled, multinational phase 3 clinical studies. Adult patients with SBS-IF with parenteral nutrition and/or intravenous fluid dependence without liver disease at baseline were randomized to treatment with the glucagon-like peptide-2 analogue teduglutide (0.05 or 0.10 mg/kg/day) or placebo subcutaneously once daily for 24 weeks. Mixed-effects models assessed the baseline predictors of change in liver chemistries. RESULTS: Between baseline and week 24, teduglutide treatment (n = 109) was associated with least squares mean reductions in aspartate aminotransferase (-7.51 IU/L; P = 0.014), alanine aminotransferase (-12.15 IU/L; P = 0.002), and bilirubin (-5.03 µmol/L [-0.057 mg/dl]; P < 0.001) compared with that of the placebo (n = 59). These values were independent of reductions in parenteral nutrition and/or intravenous fluid dependence. CONCLUSION: Teduglutide treatment was associated with reductions in liver chemistries by week 24, which is beneficial for patients with SBS-IF beyond improvements in parenteral nutrition and/or intravenous fluid dependence. Future studies should examine how long-term teduglutide might mitigate the risk of liver disease in patients with SBS-IF.

Emergence of liquid following laser melting of gold thin films.

X-ray structural science is undergoing a revolution driven by the emergence of X-ray Free-electron Laser (XFEL) facilities. The structures of crystalline solids can now be studied on the picosecond time scale relevant to phonons, atomic vibrations which travel at acoustic velocities. In the work presented here, X-ray diffuse scattering is employed to characterize the time dependence of the liquid phase emerging from femtosecond laser-induced melting of polycrystalline gold thin films using an XFEL. In a previous analysis of Bragg peak profiles, we showed the supersonic disappearance of the solid phase and presented a model of pumped hot electrons carrying energy from the gold surface to scatter at internal grain boundaries. This generates melt fronts propagating relatively slowly into the crystal grains. By conversion of diffuse scattering to a partial X-ray pair distribution function, we demonstrate that it has the characteristic shape obtained by Fourier transformation of the measured F(Q). The diffuse signal fraction increases with a characteristic rise-time of 13 ps, roughly independent of the incident pump fluence and consequent final liquid fraction. This suggests the role of further melt-front nucleation processes beyond grain boundaries.

Imaging Light-Induced Migration of Dislocations in Halide Perovskites with 3D Nanoscale Strain Mapping.

In recent years, halide perovskite materials have been used to make high-performance solar cells and light-emitting devices. However, material defects still limit device performance and stability. Here, synchrotron-based Bragg coherent diffraction imaging is used to visualize nanoscale strain fields, such as those local to defects, in halide perovskite microcrystals. Significant strain heterogeneity within MAPbBr3 (MA = CH3 NH3 + ) crystals is found in spite of their high optoelectronic quality, and both 〈100〉 and 〈110〉 edge dislocations are identified through analysis of their local strain fields. By imaging these defects and strain fields in situ under continuous illumination, dramatic light-induced dislocation migration across hundreds of nanometers is uncovered. Further, by selectively studying crystals that are damaged by the X-ray beam, large dislocation densities and increased nanoscale strains are correlated with material degradation and substantially altered optoelectronic properties assessed using photoluminescence microscopy measurements. These results demonstrate the dynamic nature of extended defects and strain in halide perovskites, which will have important consequences for device performance and operational stability.

Verwey transition as evolution from electronic nematicity to trimerons via electron-phonon coupling.

Understanding the driving mechanisms behind metal-insulator transitions (MITs) is a critical step toward controlling material's properties. Since the proposal of charge order-induced MIT in magnetite Fe3O4 in 1939 by Verwey, the nature of the charge order and its role in the transition have remained elusive. Recently, a trimeron order was found in the low-temperature structure of Fe3O4; however, the expected transition entropy change in forming trimeron is greater than the observed value, which arises a reexamination of the ground state in the high-temperature phase. Here, we use electron diffraction to unveil that a nematic charge order on particular Fe sites emerges in the high-temperature structure of bulk Fe3O4 and that, upon cooling, a competitive intertwining of charge and lattice orders arouses the Verwey transition. Our findings discover an unconventional type of electronic nematicity in correlated materials and offer innovative insights into the transition mechanism in Fe3O4 via the electron-phonon coupling.

Evaluation in a porcine wound model and long-term clinical assessment of an autologous heterogeneous skin construct used to close full-thickness wounds.

Acute and chronic wounds involving deeper layers of the skin are often not adequately healed by dressings alone and require therapies such as skin grafting, skin substitutes, or growth factors. Here we report the development of an autologous heterogeneous skin construct (AHSC) that aids wound closure. AHSC is manufactured from a piece of healthy full-thickness skin. The manufacturing process creates multicellular segments, which contain endogenous skin cell populations present within hair follicles. These segments are physically optimized for engraftment within the wound bed. The ability of AHSC to facilitate closure of full thickness wounds of the skin was evaluated in a swine model and clinically in 4 patients with wounds of different etiologies. Transcriptional analysis demonstrated high concordance of gene expression between AHSC and native tissues for extracellular matrix and stem cell gene expression panels. Swine wounds demonstrated complete wound epithelialization and mature stable skin by 4 months, with hair follicle development in AHSC-treated wounds evident by 15 weeks. Biomechanical, histomorphological, and compositional analysis of the resultant swine and human skin wound biopsies demonstrated the presence of epidermal and dermal architecture with follicular and glandular structures that are similar to native skin. These data suggest that treatment with AHSC can facilitate wound closure.

Origin of structural degradation in Li-rich layered oxide cathode.

Li- and Mn-rich (LMR) cathode materials that utilize both cation and anion redox can yield substantial increases in battery energy density1-3. However, although voltage decay issues cause continuous energy loss and impede commercialization, the prerequisite driving force for this phenomenon remains a mystery3-6 Here, with in situ nanoscale sensitive coherent X-ray diffraction imaging techniques, we reveal that nanostrain and lattice displacement accumulate continuously during operation of the cell. Evidence shows that this effect is the driving force for both structure degradation and oxygen loss, which trigger the well-known rapid voltage decay in LMR cathodes. By carrying out micro- to macro-length characterizations that span atomic structure, the primary particle, multiparticle and electrode levels, we demonstrate that the heterogeneous nature of LMR cathodes inevitably causes pernicious phase displacement/strain, which cannot be eliminated by conventional doping or coating methods. We therefore propose mesostructural design as a strategy to mitigate lattice displacement and inhomogeneous electrochemical/structural evolutions, thereby achieving stable voltage and capacity profiles. These findings highlight the significance of lattice strain/displacement in causing voltage decay and will inspire a wave of efforts to unlock the potential of the broad-scale commercialization of LMR cathode materials.

Real-space observation of fluctuating antiferromagnetic domains.

Magnetic domains play a fundamental role in physics of magnetism and its technological applications. Dynamics of antiferromagnetic domains is poorly understood, although antiferromagnets are expected to be extensively used in future electronic devices wherein it determines the stability and operational speed. Dynamics of antiferromagnets also features prominently in the studies of topological quantum matter. Real-space imaging of fluctuating antiferromagnetic domains is therefore highly desired but has never been demonstrated. We use coherent x-ray diffraction to obtain videos of fluctuating micrometer-scale antiferromagnetic domains in Ni2MnTeO6 on time scales from 10-1 to 103 s. In the collinear phase, thermally activated domain wall motion is observed in the vicinity of the Néel temperature. Unexpectedly, the fluctuations persist through the full range of the higher-temperature helical phase. These observations illustrate the high potential significance of the dynamic domain imaging in phase transition studies and in magnetic device research.

Prenatal findings and associated survival rates in fetal ventriculomegaly: A prospective observational study.

OBJECTIVES: Fetal ventriculomegaly is associated with varying degrees of genetic and structural abnormalities. The objective was to present the experience of fetal ventriculomegaly in a large European center in relation to: 1. grade of ventriculomegaly; 2. additional chromosomal/structural abnormalities; and 3. perinatal survival rates. METHODS: This was a prospective observational study of patients referred with fetal ventriculomegaly from January 2011 to July 2020. Data were obtained from the hospital database and analyzed to determine the rate of isolated ventriculomegaly, associated structural abnormalities, chromosomal/genetic abnormalities, and survival rates. Data were stratified into three groups; mild (Vp = 10-12 mm), moderate (Vp = 13-15 mm) and severe (Vp > 15 mm) ventriculomegaly. RESULTS: There were 213 fetuses included for analysis. Of these 42.7% had mild ventriculomegaly, 44.6% severe and 12.7% had moderate ventriculomegaly. Initial ultrasound assessment reported isolated ventriculomegaly in 45.5% fetuses, with additional structural abnormalities in 54.5%. The rate of chromosomal/genetic abnormalities was high,16.4%. After all investigations, the true rate of isolated VM was 36.1%. The overall survival was 85.6%. Survival was higher for those with isolated VM across all groups (P < 0.05). CONCLUSION: Ventriculomegaly is a complex condition and patients should be counselled that even with apparently isolated VM, there remains the possibility of additional genetic and/or structural problems being diagnosed in up to 10% of fetuses.

Multiscale Understanding of Surface Structural Effects on High-Temperature Operational Resiliency of Layered Oxide Cathodes.

The worldwide energy demand in electric vehicles and the increasing global temperature have called for development of high-energy and long-life lithium-ion batteries (LIBs) with improved high-temperature operational resiliency. However, current attention has been mostly focused on cycling aging at elevated temperature, leaving considerable gaps of knowledge in the failure mechanism, and practical control of abusive calendar aging and thermal runaway that are highly related to the eventual operational lifetime and safety performance of LIBs. Herein, using a combination of various in situ synchrotron X-ray and electron microscopy techniques, a multiscale understanding of surface structure effects involved in regulating the high-temperature operational tolerance of polycrystalline Ni-rich layered cathodes is reported. The results collectively show that an ultraconformal poly(3,4-ethylenedioxythiophene) coating can effectively prevent a LiNi0.8 Co0.1 Mn0.1 O2 cathode from undergoing undesired phase transformation and transition metal dissolution on the surface, atomic displacement, and dislocations within primary particles, intergranular cracking along the grain boundaries within secondary particles, and intensive bulk oxygen release during high state-of-charge and high-temperature aging. The present work highlights the essential role of surface structure controls in overcoming the multiscale degradation pathways of high-energy battery materials at extreme temperature.

Quantitative phase measurements of human cell nuclei using X-ray ptychography.

The human cell nucleus serves as an important organelle holding the genetic blueprint for life. In this work, X-ray ptychography was applied to assess the masses of human cell nuclei using its unique phase shift information. Measurements were carried out at the I13-1 beamline at the Diamond Light Source that has extremely large transverse coherence properties. The ptychographic diffractive imaging approach allowed imaging of large structures that gave quantitative measurements of the phase shift in 2D projections. In this paper a modified ptychography algorithm that improves the quality of the reconstruction for weak scattering samples is presented. The application of this approach to calculate the mass of several human nuclei is also demonstrated.

Ultra-Structural Imaging Provides 3D Organization of 46 Chromosomes of a Human Lymphocyte Prophase Nucleus.

Three dimensional (3D) ultra-structural imaging is an important tool for unraveling the organizational structure of individual chromosomes at various stages of the cell cycle. Performing hitherto uninvestigated ultra-structural analysis of the human genome at prophase, we used serial block-face scanning electron microscopy (SBFSEM) to understand chromosomal architectural organization within 3D nuclear space. Acquired images allowed us to segment, reconstruct, and extract quantitative 3D structural information about the prophase nucleus and the preserved, intact individual chromosomes within it. Our data demonstrate that each chromosome can be identified with its homolog and classified into respective cytogenetic groups. Thereby, we present the first 3D karyotype built from the compact axial structure seen on the core of all prophase chromosomes. The chromosomes display parallel-aligned sister chromatids with familiar chromosome morphologies with no crossovers. Furthermore, the spatial positions of all 46 chromosomes revealed a pattern showing a gene density-based correlation and a neighborhood map of individual chromosomes based on their relative spatial positioning. A comprehensive picture of 3D chromosomal organization at the nanometer level in a single human lymphocyte cell is presented.

Laser-induced transient magnons in Sr3Ir2O7 throughout the Brillouin zone.

Although ultrafast manipulation of magnetism holds great promise for new physical phenomena and applications, targeting specific states is held back by our limited understanding of how magnetic correlations evolve on ultrafast timescales. Using ultrafast resonant inelastic X-ray scattering we demonstrate that femtosecond laser pulses can excite transient magnons at large wavevectors in gapped antiferromagnets and that they persist for several picoseconds, which is opposite to what is observed in nearly gapless magnets. Our work suggests that materials with isotropic magnetic interactions are preferred to achieve rapid manipulation of magnetism.

Combining Multicolor FISH with Fluorescence Lifetime Imaging for Chromosomal Identification and Chromosomal Sub Structure Investigation.

Understanding the structure of chromatin in chromosomes during normal and diseased state of cells is still one of the key challenges in structural biology. Using DAPI staining alone together with Fluorescence lifetime imaging (FLIM), the environment of chromatin in chromosomes can be explored. Fluorescence lifetime can be used to probe the environment of a fluorophore such as energy transfer, pH and viscosity. Multicolor FISH (M-FISH) is a technique that allows individual chromosome identification, classification as well as assessment of the entire genome. Here we describe a combined approach using DAPI as a DNA environment sensor together with FLIM and M-FISH to understand the nanometer structure of all 46 chromosomes in the nucleus covering the entire human genome at the single cell level. Upon DAPI binding to DNA minor groove followed by fluorescence lifetime measurement and imaging by multiphoton excitation, structural differences in the chromosomes can be studied and observed. This manuscript provides a blow by blow account of the protocol required to perform M-FISH-FLIM of whole chromosomes.

X-ray Ptychography Imaging of Human Chromosomes After Low-dose Irradiation.

Studies of the structural and functional role of chromosomes in cytogenetics have spanned more than 10 decades. In this work, we take advantage of the coherent X-rays available at the latest synchrotron sources to extract the individual masses of all 46 chromosomes of metaphase human B and T cells using hard X-ray ptychography. We have produced 'X-ray karyotypes' of both heavy metal-stained and unstained spreads to determine the gain or loss of genetic material upon low-level X-ray irradiation doses due to radiation damage. The experiments were performed at the I-13 beamline, Diamond Light Source, Didcot, UK, using the phase-sensitive X-ray ptychography method.

Review of the Technical, Toxicological, and PKPD Considerations for Conducting Inhalation Toxicity Studies on Biologic Pharmaceuticals-The Outcome of a Cross-Industry Working Group Survey.

The inhaled route is still a relatively novel route for delivering biologics and poses additional challenges to those encountered with inhaled small molecules, further complicating the design and interpretation of toxicology studies. A working group formed to summarize the current knowledge of inhaled biologics across industry and to analyze data collated from an anonymized cross-industry survey comprising 12 inhaled biologic case studies (18 individual inhalation toxicity studies on monoclonal antibodies, fragment antibodies, domain antibodies, oligonucleotides, and proteins/peptides). The output of this working group provides valuable insights into the issues faced when conducting toxicology studies with inhaled biologics, including common technical considerations on aerosol generation, use of young and sexually mature nonhuman primates, pharmacokinetic/pharmacodynamic modeling, exposure and immunogenicity assessment, maximum dose setting, and no observed adverse effect levels determination. Although the current data set is too small to allow firm conclusions, testing of novel biologics remains an active area and is likely to remain so for molecules where delivery via the inhaled route is beneficial. In the future, it is hoped others will continue to share their experiences and build on the conclusions of this review to further improve our understanding of these complex issues and, ultimately, facilitate the safe introduction of inhaled biologics into clinical use.