The BoneXpert method for automated determination of bone age from hand X-rays was introduced in 2009 and is currently running in over 200 hospitals. The aim of this work is to present version 3 of ...the method and validate its accuracy and self-validation mechanism that automatically rejects an image if it is at risk of being analysed incorrectly. The training set included 14,036 images from the 2017 Radiological Society of North America (RSNA) Bone Age Challenge, 1642 images of normal Dutch and Californian children, and 8250 images from Tübingen from patients with Short Stature, Congenital Adrenal Hyperplasia and Precocious Puberty. The study resulted in a cross-validated root mean square (RMS) error in the Tübingen images of 0.62 y, compared to 0.72 y in the previous version. The RMS error on the RSNA test set of 200 images was 0.45 y relative to the average of six manual ratings. The self-validation mechanism rejected 0.4% of the RSNA images. 121 outliers among the self-validated images of the Tübingen study were rerated, resulting in 6 cases where BoneXpert deviated more than 1.5 years from the average of the three re-ratings, compared to 72 such cases for the original manual ratings. The accuracy of BoneXpert is clearly better than the accuracy of a single manual rating. The self-validation mechanism rejected very few images, typically with abnormal anatomy, and among the accepted images, there were 12 times fewer severe bone age errors than in manual ratings, suggesting that BoneXpert could be safer than manual rating.
Phase relations have been derived for the Sc-rich parts of the ternary systems Sc-T-Ga at 850 °C (T = Mn,Fe,Co,Ni) as well as for the corresponding regions of the pertinent binary systems. "Sc4Mn" ...was not observed, but hexagonal Sc2Ga (space group P63mc, unique type) is a binary phase (at 29–31 at% Ga) with a peritectic decomposition temperature (at 1075 °C) close to the corresponding eutectic with scandium at 1065 °C and 17.5 at% Ga. Electron microprobe analyses (EPMA) revealed very limited solid solubilities at 850 °C of T-elements in Sc (<2 at% T). Although the maximal solubility of Ga in Sc at 850 °C is about 1 at% Ga, it renders the Sc-phase brittle. An X-ray single crystal structure analysis and TEM investigation defined Sc2+xNi1−x (x = 0.15) as a highly disordered Ti2Ni-type related to the type of disorder known for Dy5Pd2. Whereas the isothermal ternary sections for Sc-{Mn,Fe}-Ga are characterized by one ternary compound, Sc54{Mn,Fe,Ga}17 with the orthorhombic Hf54Os17-type (space group Immm), the systems with Co, Ni contain a so-called kappa (κ) phase, Sc10(Co1−xGax)3Co and Sc10(Ni1−xGax)3Ni. Both phases are occupation variants of the κ-Hf9Mo4B-type (space group P63/mmc). Besides that, the Sc-Co-Ga system at 850 °C comprises also a hitherto unknown representative of the Hf54Os17-type as well as two further ternary solid solution phases: Sc15−x−y□yCo3+x−zGa1+z (unique structure type, space group Immm; x = 1.60, y = 0.58; 0 ≤z ≤ 0.82) and Sc50+xCo13−zGa3+z (ε-Mg26−xAg7+x type, space group Fm-3; x = 0.84; 0 ≤z ≤ 1). For all compounds the crystal structures were derived from X-ray single crystal studies, some even at several compositions. The characteristic features of all structure types are non-regular Sc-icosahedra centered by (T,Ga) atoms. Whereas κ-Sc10(T1−xGax)3T phases (T = Co,Ni) form a typical network of corner-connected empty octahedra Sc6, which encompass Sc-centered icosahedra Sc6Ga6 and T-centered trigonal prisms TSc6, the Sc54(T,Ga)17 phases are made of (T,Ga)-centered defect icosahedron-clusters (T = Mn,Fe,Co). The ternary compounds exhibit remarkable large homogeneity regions mainly at practically constant Sc-contents i.e. deviating only slightly from T/Ga exchange pointing towards Sc-richer limits: at 850 °C from 12 to 14.6 at% Ga for the Co-κ-phase and from 2.1 to 15.4 at% Ga for the Ni-κ-phase; from about 6–12 at% for the phases Sc54{Mn,Co,Ga}17, but from 2.8 to 12.3 at% Ga in the case of Sc54{Fe,Ga}17. It should be mentioned that Sc54{Fe,Ga}17 as well as κ-Sc10(Ni,Ga)4 approach the corresponding binary system almost joining with binary cubic Sc29Fe6 or at least indicating a vanishing instability for the binary hypothetical kappa phase “Sc10Ni4”. Physical properties have been studied for the compounds richest in Sc: specific heat and electrical conductivity measurements infer metallic behavior for the Sc54(T,Ga)17 phases. Whereas Sc54Fe9.4Ga7.6 and Sc54Co7.3Ga9.7 are almost temperature independent paramagnets, Sc54Mn8.5Ga8.5 exhibits an approximate Curie-Weiss behavior: χ0 = 1.03 × 10−3 emu/mol; Θp = 15.8 K, µeff = 2.23 µB/Mn. At low temperatures it reveals a weakly interacting spin glass system with a spin-freezing anomaly at around 8 K. Hardness and elastic moduli are in the range of typically polar intermetallics. Chemical bonding and charge transfer is elucidated from DFT calculations and eDOS for the kappa phases, Sc10(Co1−xGax)3Co (x = 0, 0.67, 1), Sc10(Ni1−xGax)3Ni (x = 0.67), as well as for the compounds with selected composition Sc54{Mn,Fe,Co}10Ga7 and showed high electron localization inside the empty Sc6 octahedra for all studied compounds and related kappa phases, which may attract small and highly electronegative elements.
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•Binary systems corrected: novel structure Sc2Ga, no “Sc4Mn”, disordered Sc2+xNi1-x.•Phase relations at 850°C in the Sc-corner of the four systems Sc-{Mn,Fe,Co,Ni}-Ga.•Novel ternary compounds: Sc54(Co,Ga)17; Sc15-x-y□yCo3+x-zGa1+z, Sc50+xCo13-zGa3+z.•Single crystal X-ray analyses: Sc54{T,Ga}17 (T=Mn,Fe); κ-Sc10{T,Ga}3T (T=Co,Ni).•Experimental Cp, rho, Chi, elastic moduli, HV of ternary phases.•DFT calculations define the heat of formation, mechanical properties, eDOS and ELF.
...of these recommendations, the publications previously known as “Expert Consensus Documents” were rebranded as “Expert Consensus Decision Pathways.” While no specific number of Expert Consensus ...Decision Pathways has been established for a given year, the oversight committee considers the limitations in resources and the acuity of the need for guidance in determining which topics will be pursued and which will be deferred or referred to other College committees for action.4 Content Development Work Groups Content Development Work Groups support the creation of Expert Consensus Decision Pathways. Because Expert Consensus Decision Pathways are a type of ACC clinical policy, those selected to support these efforts will adhere to the same standards outlined in ACC’s relationships with industry (RWI) policy for ACC-led clinical policy documents (see Section 4.3 Relationships With Industry for additional details). Responsibilities of the chair are detailed in Table 2.4.2 Content Development Work Group Selection Content Development Work Groups are selected by the oversight committee chairs in coordination with the Chair of the Science and Quality Committee. Because of the varied subject matter of Expert Consensus Decision Pathways, the number of members differs from one to another, but is generally limited to 5 to 7 members. ...existing Expert Consensus Decision Pathways are reviewed for need of update.
Many of these new pharmacological therapies are costly and prior authorization may be required by payers prior to prescribing these agents. ...the College convened a roundtable focused on 1) ...strategies to facilitate effective prior authorization of novel and emerging therapies; and 2) identification of high-risk patients who are appropriate candidates for these therapies. Figure 5 provides an overview of the firewall specifications preventing involvement in roundtable planning by industry supporters. Because the ACC adheres to a very strict conflict of interest policy to prevent any influence by financial supporters, all travel and food for participants is paid for directly by the ACC and is not associated with any industry funding. ...participants are not subject to reporting under the Physician Payments Sunshine Act or disclosure of relationships with industry in the ACC’s database. ...the ACC developed and published an Expert Consensus Decision Pathway on Periprocedural Management of Anticoagulation in Patients with Atrial Fibrillation (50).
Context: A protein polymorphism of the GH receptor (GHR) based on the genomic deletion of exon 3 (d3-GHR) has recently been linked to the magnitude of growth response to high-dose recombinant human ...GH (rhGH) therapy of short children without GH deficiency.
Objective: This study tests the novel association in two distinct groups of rhGH-treated patients, short girls with Turner syndrome and short children born small for gestational age (SGA).
Design: The retrospective study included all children who were treated with rhGH during the last 18 yr at our hospital.
Patients: Patients with Turner syndrome were defined by the specific karyotype (n = 53), short children born SGA were determined by birth length and/or weight less than −2.0 sd score and a height at start of rhGH therapy less than −2.0 sd score (n = 60). Exclusion criteria were puberty, an age less than 3.5 or more than 14 yr, and GH deficiency.
Materials and Methods: Growth prediction for the first year of therapy was calculated on the basis of rhGH dose, age, weight, height, and gender-adjusted midparental height according to the prediction models by Ranke et al. The GHR-exon 3 locus was genotyped using a PCR multiplex assay. GH, IGF-I, and IGF binding protein 3 (IGFBP-3) were measured by RIA.
Intervention: For growth promotion, a mean rhGH dose of 38 μg/kg·d (sd, ±8) was administered in Turner syndrome patients and 56 μg/kg·d (sd, ±11) in short children born SGA.
Results: No significant difference in height, spontaneous height velocity, IGF-I, and IGFBP-3 levels was found at the start of rhGH therapy in the three GHR genotype groups studied. At the first year of treatment, girls with Turner syndrome carrying one or two d3-GHR alleles showed a significantly higher increment in height velocity (P = 0.019) and exceeded their growth prediction significantly (P = 0.007), whereas their increments of IGF-I and IGFBP-3, weight, and height were not significantly different. Carriers of d3-GHR in the group of short children born SGA grew significantly faster than predicted (P = 0.023). However, in comparison to the carriers of full-length GHR, gain of height velocity was not significantly higher (P = 0.067). The mean gain of height associated with d3-GHR accounted for approximately 0.75 cm in SGA and 1.5 cm in Turner syndrome during the first year of rhGH therapy.
Conclusions: Our data support the theory that there is increased responsiveness to high-dose rhGH in association with the d3-GHR genotype. The magnitude of this effect may depend on the primary origin of the short stature.
Recovery from viral encephalomyelitis requires immune-mediated noncytolytic clearance from neurons by mechanisms assumed to be the same for all neurons. In alphavirus encephalomyelitis, antibody ...clears infectious virus from neurons in all regions of the central nervous system (CNS), but CD8 T cells contribute to elimination of viral RNA. To understand the role of T cells in clearance, we infected antibody knockout mice with Sindbis virus. Virus was cleared from spinal cord and brain stem neurons, but not from cortical neurons, and required both CD4 and CD8 T cells. Infection with cytokine-expressing recombinant viruses suggested that T cells used interferon-γ, but not tumor necrosis factor α, in clearing virus and that populations of neurons differ in responsiveness to this effector pathway.
This review examines the role of skeletal maturity ('bone age', BA) assessment in clinical practice. BA is mainly used in children with the following conditions: short stature (addressed in part 1 of ...this review), tall stature, early or late puberty, and congenital adrenal hyperplasia (all addressed in part 2). Various manual and automatic methods of BA assessment have been developed. Healthy tall children tend to have advanced BA and healthy short children tend to have delayed BA in comparison to chronological age. Growth hormone (GH) treatment of children with GH deficiency leads to a catch-up in BA that is usually appropriate for the height of the child. Response to GH is dependent on BA delay in young children with idiopathic short stature, and GH dosage appears to affect BA acceleration. In chronic renal failure, BA is delayed until puberty but then increases due to increased sensitivity of the growth plate to sex steroids, thus further impairing adult height. The assessment of BA provides an important contribution to the diagnostic workup and management of children with short stature.
Context: Severe congenital GH deficiency (GHD) of the newborn is a rare disease, which can cause life-threatening hypoglycemias beginning in the first week of life. Reviews and consensus papers on ...the diagnosis of GHD repeatedly state the lack of a practical evidence-based approach to the diagnosis of GHD in the newborn.
Objective: Here we provide for the first time sound reference values and a diagnostic cutoff for the GH levels in newborns at the age between d 3 and 5.
Design, Setting, and Patients: GH was measured in the eluate from 314 filter papers of the newborn screening test performed in our university hospital by using a highly sensitive human GH-ELISA. Reference data are compared with measurements from nine newborns with very high likelihood of having severe GHD, and cutoffs for the diagnostic work-up are defined.
Results: In the presence of clinical evidence, the diagnosis of neonatal GHD can be confirmed during the first week of life by a single randomly taken GH level less than 7μg/liter with 100% sensitivity and 98% specificity on the basis of our assay method. GH content in newborn screening cards stored for almost 3 yr were not different from the content found in recently used screening cards indicating high immunological stability of GH over time. Therefore, the diagnostic approach can use stored screening cards. In addition, we observed a clear gender dichotomy in respect to GH, with healthy female newborns having significantly higher GH levels than males. Cigarette smoking during pregnancy was associated with higher, transient tachypnea of the newborn with lower GH levels.
Conclusions: We provide the first rational approach to the diagnosis of severe GHD in the newborn and evidence for gender dichotomy of the neonatal GH axis.
This study provides the first rational approach to the diagnosis of severe GHD in the newborn and evidence for gender dichotomy of the neonatal GH axis.
Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current ...methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.
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