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Abstract: Background: Spinal cord injury affects walking balance control, which necessitates methods to quantify balance ability. The purposes of this study were to 1) examine walking balance through foot placement variability post-injury; 2) assess the relationship between measures of variability and clinical balance assessments; and 3) determine if spatial parameter variability might be used as a clinical correlate for more complex balance measurements. Methods: Ten persons with spinal cord injury walked without devices on a split-belt treadmill at self-selected speeds. Ten healthy controls walked at 0.3 and 0.6m/s for comparison. Variability of step width and length, anteroposterior and mediolateral foot placements relative to center-of-mass, and margin-of-stability were calculated. Clinical assessments included Berg Balance Scale and Dynamic Gait Index. Findings: Participants with spinal cord injury demonstrated significantly different variability in all biomechanical measures compared to controls (P ≤0.007). Berg Balance Scale scores were significantly inversely associated with step length as well as anteroposterior and mediolateral foot placement variability (P ≤0.05). Dynamic Gait Index scores were significantly inversely associated with mediolateral foot placement variability (P ≤0.05). Participants with spinal cord injury showed significant correlations between spatial parameter variability and all other measures (P ≤0.005), except between step length and margin-of-stability (P =0.068); controls revealed fewer correlations. Interpretation: Persons post-spinal cord injury exhibit an abnormal amount of stepping variability when challenged to walk without devices, yet preserve the ability to avoid falling. When complex laboratory measures of variability are unavailable clinically, spatial parameter variability or standardized balance assessments may be plausible indicators of walking balance control. [Copyright &y& Elsevier]

Background: Frailty is a state of increased vulnerability to health-related stressors and can be measured by summing the number of frailty characteristics present in an individual. Discharge institutionalization (rather than discharge to home) represents disease burden and functional dependence after hospitalization. Our aim was to determine the relationship between frailty and need for postoperative discharge institutionalization. Study Design: Subjects ≥65 years undergoing major elective operations requiring postoperative ICU admission were enrolled. Discharge institutionalization was defined as need for institutionalized care at hospital discharge. Fourteen preoperative frailty characteristics were measured in 6 domains: comorbidity burden, function, nutrition, cognition, geriatric syndromes, and extrinsic frailty. Results: A total of 223 subjects (mean age 73 ± 6 years) were studied. Discharge institutionalization occurred in 30% (n = 66). Frailty characteristics related to need for postoperative discharge institutionalization included: older age, Charlson index ≥3, hematocrit <35%, any functional dependence, up-and-go ≥15 seconds, albumin <3.4 mg/dL, Mini-Cog score ≤3, and having fallen within 6 months (p < 0.0001 for all comparisons). Multivariate logistic regression retained prolonged timed up-and-go (p < 0.0001) and any functional dependence (p < 0.0001) as the variables most closely related to need for discharge institutionalization. An increased number of frailty characteristics present in any one subject resulted in increased rate of discharge institutionalization. Conclusions: Nearly 1 in 3 geriatric patients required discharge to an institutional care facility after major surgery. The frailty characteristics of prolonged up-and-go and any functional dependence were most closely related to the need for discharge institutionalization. Accumulation of a higher number of frailty characteristics in any one geriatric patient increased their risk of discharge institutionalization. [Copyright &y& Elsevier]

Abstract: Protein-based vaccines have emerged as a potentially promising approach for the generation of antigen-specific immune responses. However, due to their low immunogenicity, there is a need for innovative approaches to enhance protein-based vaccine potency. One approach to enhance protein-based vaccine potency is the employment of toll-like receptor ligands, such as CpG oligonucleotides, to activate the antigen-specific T cell immune responses. Another approach involves employing a method capable of improving the delivery of protein-based vaccine intramuscularly to lead to the slow release of the protein, resulting in improved vaccine potency. In the current study, we aimed to determine whether intramuscular injection of protein-based vaccines in conjunction with CpG followed by electroporation can lead to increased delivery of the protein-based vaccine into muscle cells, resulting in enhanced protein-based vaccine potency. We found that intramuscular injection followed by electroporation can effectively transduce the protein-based vaccine into the muscle cells. Furthermore, we found that intramuscular vaccination with OVA protein in combination with CpG followed by electroporation generates the best OVA-specific CD8+ T cell immune responses as well as the best protective and therapeutic antitumor effects in vaccinated mice. CD8+ T cells were found to play an important role in the observed protective antitumor effects generated by the vaccination. Similar results were observed using the HPV-16 E7 protein-based vaccination system. Thus, our data indicate that intramuscular administration of protein-based vaccines in conjunction with CpG followed by electroporation can significantly enhance the antigen-specific CD8+ T cell immune responses. The clinical implications of the study are discussed. [ABSTRACT FROM AUTHOR]

Abstract: This article presents a simplified means of controlling the experiment-wise risk of declaring too many effects active when analyzing an unreplicated orthogonal design. The method begins by assuming a lower bound on the number of null effects. The regression method of backward elimination is followed, comparing each F statistic with a common critical value, until the first statistically significant outcome. By using a single critical value, the method is simpler than the approach of and and is sometimes more powerful. Simulation is used to demonstrate the actual risk of Type I errors and power under various configurations of the true regression coefficients. [Copyright &y& Elsevier]

Abstract: Let be a connected graded algebra and let denote its Ext-algebra . There is a natural -structure on , and we prove that this structure is mainly determined by the relations of . In particular, the coefficients of the -products restricted to the tensor powers of give the coefficients of the relations of . We also relate the ’s to Massey products. [Copyright &y& Elsevier]

Single phase of La1−xSrxCoO3 (LSCO) with 0.1 ≤ x ≤ 0.4 have been prepared by the solid-state reaction method. All samples have the R3̅c symmetry. There is no phase transition detected at the temperature range from 10 to 300 K. The variations of the local bond-lengths of Co—O in CoO6 octahedron and lattice parameter ar confirm that hole-doping stabilize the intermediate-spin (IS) state of Co ions. The magnetic phase diagram is well understood in terms of phase separation scenario. Qualitatively, hole-rich ferromagnetic (FM) clusters increasing in size and number with the increase in the concentration of Sr at the expensive of non-FM insulating matrix, and percolating at the vicinity of 0.15, are suggested to explain the onset of FM order and insulator–metal transition. In addition, the values of effective paramagnetic moment μeff also strongly prove the presence of IS spin state of Co in our system. Very small magnetoresistance (MR), 5% with 3 T magnetic field applied, is obtained. This MR response indicates that a distinct mechanism is likely to dominate in LSCO compared to that in mixed-valence manganites. [Copyright &y& Elsevier]

Abstract: The use of the thiazolidinedione insulin sensitizers rosiglitazone and pioglitazone for the treatment of type 2 diabetes mellitus in recent years has proven to be effective in helping patients resume normal glycemic control. However, their use is often associated with undesirable side effects including peripheral edema, congestive heart failure and weight gain. Here, we report the identification and characterization of a novel selective PPARγ modulator, SPPARγM5 ((2S)-2-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl} phenoxy)propionic acid), which has notable insulin sensitizing properties and a superior tolerability profile to that of rosiglitazone. SPPARγM5 is a potent ligand of human PPARγ with high selectivity versus PPARα or PPARδ in receptor competitive binding assays. In cell-based transcriptional activation assays, SPPARγM5 was a potent partial agonist of human PPARγ in comparison to the PPARγ full agonist rosiglitazone. Compared to rosiglitazone or the PPARγ full agonist COOH (2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid), SPPARγM5 induced an attenuated PPARγ-regulated gene expression profile in fully differentiated 3T3-L1 adipocytes and white adipose tissue of chronically treated db/db mice. SPPARγM5 treatment also reduced the insulin resistance index by homeostasis model assessment (HOMA), suggesting an improvement in insulin resistance in these db/db mice. Treatment of obese Zucker rats with either rosiglitazone or SPPARγM5 resulted in an improvement in selected parameters that serve as surrogate indicators of insulin resistance and hyperlipidemia. However, unlike rosiglitazone, SPPARγM5 did not cause significant fluid retention or cardiac hypertrophy in these rats. Thus, compounds such as SPPARγM5 may offer beneficial effects on glycemic control with significantly attenuated adverse effects. [Copyright &y& Elsevier]

Abstract: Directional solidification (DS) of a binary Mg–4Al (wt.%) alloy was carried out to investigate the microstructures and microsegregation under controlled solidification conditions. In directional solidification the microstructure depends on the growth rate V because the cooling rate, which governs the solidification microstructure, is the product of the growth rate and the temperature gradient. The ability to produce simple and uniform microstructures in directional solidification enables us to correlate the formation of the microstructure and its characteristic length scales quantitatively with processing parameters. The morphology of the solid–liquid interface and the microstructure of both the mushy zone and the steady-state region were characterized at different levels of growth rates. With the help of an electron microprobe, microsegregation was determined in a specimen directionally solidified with cooling rates ranging from 0.06 to 0.8K/s. The calculated microsegregation results based on the Scheil model deviated significantly from the experimental data, which is anticipated since back diffusion was not included due to the lack of diffusivity data. [Copyright &y& Elsevier]

Abstract: The reaction of 1-alkyl-2-(naphthyl-(α/β)-azo)imidazoles [α-NaiR, (1) and β-NaiR (2) where R=Me (a), Et (b), CH2Ph (c)] with Co(OAc)2 ·4H2O and NaN3 in methanol solution has synthesised [Co(α/β-NaiR)2(N3)2] (3, 4). The complexes have been characterized by spectroscopic data and structurally confirmed by single crystal X-ray diffraction data in the case of [Co(β-NaiEt)2(N3)2] (4b). The structure is a severely distorted tetrahedron of CoN4 coordination in which β-NaiEt serves as a monodentate imidazole-N donor ligand. The distortion arises from two weak interactions from Co⋯N(azo) (N(azo) from β-NaiEt). Two weak transitions observed at >600nm are due to the structural distortion. Cyclic voltammetry shows a high potential Co(III)/Co(II) couple along with ligand reductions in the complexes. The tris-chelates, [Co(NaiR)3]2+, are also characterized. [Copyright &y& Elsevier]

Tubulointerstitial nephritis is a cardinal renal manifestation in leptospirosis and LipL32, the major lipoprotein component of leptospiral outer membrane proteins (OMPs), induces a robust inflammatory response in cultured renal proximal tubule cells through a nuclear factor-κB-related pathway. Here, we investigated whether Toll-like receptor (TLR), known to play a pivotal role in innate immunity, could mediate the inflammatory response induced by leptospiral OMPs in renal proximal tubule cells. TLR expression was analyzed by flow cytometry and indirect immunofluorescence in cultured mouse proximal tubule (pyruvate kinase simian virus 40-proximal straight (PKSV-PR)) cells. Reverse transcription-competitive polymerase chain reaction and enzyme-linked immunosorbent assay were undertaken to analyze the inducible effects of inducible nitric oxide synthase (iNOS) and monocyte chemoattractant protein-1 (MCP-1 also termed CCL2) by pathogenic and non-pathogenic leptospiral OMPs and recombinant lipoproteins in either PKSV-PR cells or TLR-transfected human embryonic kidney (HEK) 293 cells. Anti-TLR antibodies were used for blocking experiments. Leptospira santarosai serovar Shermani OMPs and LipL32 induced a significant increase in TLR2 but not TLR4 expression in PKSV-PR cells. The increase in iNOS and CCL2/MCP-1 mRNA expressions could be prevented by an anti-TLR2 antibody, but not by an anti-TLR4 antibody. Furthermore, leptospiral OMPs stimulated both CCL2/MCP-1 mRNA and secreted protein in transfected HEK 293 cells with a TLR2-expressing plasmid, but had no effect in cells with a TLR4-expressing plasmid. In conclusion, these findings indicate that the stimulation of iNOS and CCL2/MCP-1 caused by pathogenic leptospiral OMPs, in particular LipL32, in proximal tubule cells requires TLR2 for the early inflammatory response.Kidney International (2006) 69, 815–822. doi:10.1038/sj.ki.5000119; published online 25 January 2006 [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we have calculated the third-order nonlinear optical polarizabilities corresponding to three optical processes: third-harmonic generation (THG), electric-field-induced second-harmonic generation (EFISHG) and degenerate four-wave mixing (DFWM) for B12N12, B24N24 and B36N36 clusters. The calculations have been performed by employing ab initio time-dependent density functional theory combined with sum-over-states method (SOS//TDDFT). We obtained the similar dynamic behavior of third-order NLO polarizabilities for three BN clusters. At input photon energy below 1.25eV, the resonance enhancements of response haven''t occurred. This is due to the fact that the calculated BN clusters have the large transition energy. B24N24 cluster has the larger transition dipole moments and the third-order polarizabilities of B24N24 are much larger than those of B12N12 and B36N36. We also estimate the static third-order optical susceptibility χ (3) for BN fullerene materials from the average static third-order polarizability <γ>. The static χ (3) of B24N24 fullerene materials are 1.36×10−14 esu for three NLO processes. [Copyright &y& Elsevier]

The reaction sequence of 3He(α,γ)7Be(α,γ)11C(p,γ)12N to CNO could be an alterative way of 3α →12C to convert 3He into CNO. It may become important in some specific environments, such as in a very massive star with low metallicity. Whether it is significant depends on the reactions involved, one of the important reactions is the 11C p-capture competing with its β + decay. The S factor for the 11C(p,γ)12N direct capture was obtained in our previous work. This work is to update the reaction rate by adding uncertainty and fitting with the Thielemann format. With the new rate, nucleosynthesis simulations are performed to study the bridge of the p-p chains to CNO through the above sequence. [Copyright &y& Elsevier]

Abstract: The melanocortin 4 receptor (MC4R) plays a critical role in the regulation of energy homeostasis, and the MC4R knockout mouse and humans with MC4R defective mutations in only one allele indicate that there is a gene dosage effect. Alterations in gene expression levels for MC4R could, therefore, have significant effects on energy homeostasis. To begin to develop a mouse model for studies on MC4R promoter in situ we used ∼1kb mouse MC4R promoter together with 426bp MC4R 5′ UTR, previously shown to support basal expression of reporter gene transcription in cell lines with endogenous MC4R mRNA, and fused this DNA to a nuclear localized LacZ reporter gene. The construct was injected into pronuclei from FVB mice. Five transgenic lines were identified as carrying autosomal transgene insertions; three of these had significant β-galactosidase staining in brain and in a few cells in the heart but not in kidney, liver, lung, gonadal fat or testis. The pattern of transgene expression in the brain differed markedly for the three lines, and in one of these lines was remarkably similar to endogenous MC4R mRNA expression observed using in situ hybridisation. In conclusion, ∼1kb mouse MC4R promoter is sufficient to direct gene expression to the brain including regions that express endogenous MC4R mRNA. [Copyright &y& Elsevier]

Abstract: Configurations of four [5, 6]-open C60 monoadducts have been optimized at B3LYP/6-31G* level. The calculated geometrical structures show that the bonds at the junction between five- and six-membered rings break and the planar properties of pentagon and hexagon rings in the vicinity of functionalized groups disappear for these C60 derivatives. On the basis of the optimized geometrical structures, their excitation energies and third-order nonlinear optical polarizabilities have been calculated at TDB3LYP/3-21G* level coupled with sum-over-states method for these C60 monoadducts. The obtained results show that different functionalized groups result in different effects on HOMO–LUMO gap and different optical property for [5, 6]-open C60 derivatives. The absorption spectra of the derivatives, in which a nitrogen atom bridges the functionalized groups to C60 cage, show a red shift compared with those of the derivatives in which a carbon atom becomes as the connection. [Copyright &y& Elsevier]

Two compounds Zn3B2O6 and KZn4B3O9 were synthesized by high temperature solution reaction with different experiment routes from references. The crystal structure of Zn3B2O6 was refined and it crystallizes in monoclinic space group with cell dimensions a = 23.826Å b = 5.4033Å c = 8.3826Å β = 102.912, V = 981.8Å and Z = 8, μ = 14.49cm-1, Dcalcd 4.425cm-3.The UV–vis DRIS (ultraviolet–visible diffuse reflection integral spectrum), fluorescent spectra of two compounds have been studied. The calculated results of crystal energy band structure by the DFT method show that the solid state compounds of both Zn3B2O6 and KZn4B3O9 are isolators with direct band gaps. The calculated total and partial density of states indicate that the top valence bands are contributions from the mixings of O-2p, B-2p and Zn-3d states and low conduction bands mostly originate from Zn-4s states. The Bre pure covalence and Znre mostly ionic interactions, and the ionic interaction strength is stronger between the Ktween the Kzn4B3O9. The calculated optical response functions expect that these two compounds have width light transmission from the near ultraviolet (UV) to infrared (IR) light zone, and the average refractive index are 1.41 and 1.39 for Zn3B2O6 and KZn4B3O9 crystals, respectively. [Copyright &y& Elsevier]

The urokinase-type plasminogen activator receptor (uPAR) is released from human cancers and is readily detected in blood. In animal models, soluble uPAR (SuPAR) antagonizes cancer progression; however, the mechanism by which SuPAR functions in vivo remains unclear. It is generally thought that SuPAR scavenges uPA and prevents its interaction with membrane-anchored uPAR. In this study, we demonstrate a novel molecular mechanism by which SuPAR may inhibit cancer progression. We show that SuPAR has the potential to directly and in a uPA-independent manner block the signaling activity of membrane-anchored uPAR. Whether SuPAR inhibits signaling is cell type-specific, depending on the state of the endogenous uPA-uPAR signaling system. In uPAR-deficient cells that lack endogenous uPAR signaling, including uPAR-/- murine embryonic fibroblasts and human embryonal kidney 293 cells, SuPAR functions as a partial signaling agonist that activates ERK/mitogen-activated protein kinase. By contrast, in cells with potent autocrine uPA-uPAR signaling systems, including MDA-MB 231 breast cancer cells and low density lipoprotein receptor-related protein-1-deficient murine embryonic fibroblasts, SuPAR substantially decreases ERK activation. The mechanism probably involves competitive displacement of membrane-anchored uPAR-uPA complex from signaling adaptor proteins. As a result of its effects on cell signaling, SuPAR blocks cell growth and inhibits cellular invasion of Matrigel™. Cleavage of SuPAR by proteinases increases its signaling agonist activity and reverses its inhibitory effects on growth and invasion. Thus, proteolytic cleavage represents a molecular switch that neutralizes the anticancer activity of SuPAR. [ABSTRACT FROM AUTHOR]

Configurations of C60 fullerene derivatives (C60COOCH2, C60COOHCH3) are optimized using B3LYP method at 6–31G* level. The calculated charge distributions by Natural Population Analysis show that the charge transfers exist between the functionalized group and parent C60. Then, the excited state properties of title species are calculated by the time-dependent density functional theory. It is shown that the fullerene derivatives make a small red shift of the absorption spectra in comparison with the C60 cage itself and the calculated electronic absorption spectra are in good agreements with their observed values. [Copyright &y& Elsevier]

We employ an ab initio time-dependent Hartree–Fock (TDHF) formalism combined with sum-over-states (SOS) method to calculate the linear and nonlinear optical properties of direct semiconductor clusters. The obtained electronic absorption spectra predict a variety of the spectral shapes and peak positions and an increase of the second-order nonlinear optical response with an increase of V-group ionic radius in the title clusters. Charge transfers from the π bonding to π antibonding orbitals between III and V group atoms make a significant contribution to the second-order polarizability. [Copyright &y& Elsevier]

A numerical model was used to investigate the effect of spatial variability in fracture permeability on liquid seepage and moisture distribution in the vicinity of a waste emplacement drift in the unsaturated zone (UZ) of Yucca Mountain. The model is based on a two-dimensional, cross-sectional, dual-permeability model of the unsaturated zone at Yucca Mountain and uses a stochastic approach to investigate the effect of small-scale heterogeneous features. The studies were conducted using one uniform fracture permeability case, three realizations of stochastically generated fracture permeability, one discrete permeability feature case, and one increased ambient liquid flux case. In all cases, the models predict that completely dry drift conditions will develop above and below the drift in 10–100 years and remain dry for 1000–2000 years. During this period, the models predict no seepage into drifts, although liquid flux above the drifts and within the drift pillars may increase by up to two orders of magnitude above ambient flux. This is because the heat released by the emplaced waste is sufficient to vaporize liquid flux of one to two orders of magnitude higher than present-day ambient flux for over 1000 years. The results also show that unsaturated zone thermal–hydrological (TH) models with uniform layer permeability can adequately predict the evolution of seepage and moisture distribution in the rock mass surrounding the repository drifts. The models further show that although variability in fracture permeability may focus and enhance liquid flow in regions of enhanced liquid saturation (due to condensation above the drifts), vaporization and vapor diffusion can maintain a dry environment within the drifts for thousands of years. [Copyright &y& Elsevier]

The U.S. Department of Energy (DOE) is actively investigating the technical feasibility of permanent disposal of high-level nuclear waste in a repository to be situated in the unsaturated zone (UZ) at Yucca Mountain (YM), Nevada. In this study we investigate, by means of numerical simulation, the transport of radioactive colloids under ambient conditions from the potential repository horizon to the water table. The site hydrology and the effects of the spatial distribution of hydraulic and transport properties in the Yucca Mountain subsurface are considered. The study of migration and retardation of colloids accounts for the complex processes in the unsaturated zone of Yucca Mountain, and includes advection, diffusion, hydrodynamic dispersion, kinetic colloid filtration, colloid straining, and radioactive decay. The results of the study indicate that the most important factors affecting colloid transport are the subsurface geology and site hydrology, i.e., the presence of faults (they dominate and control transport), fractures (the main migration pathways), and the relative distribution of zeolitic and vitric tuffs. The transport of colloids is strongly influenced by their size (as it affects diffusion into the matrix, straining at hydrogeologic unit interfaces, and transport velocity) and by the parameters of the kinetic-filtration model used for the simulations. Arrival times at the water table decrease with an increasing colloid size because of smaller diffusion, increased straining, and higher transport velocities. The importance of diffusion as a retardation mechanism increases with a decreasing colloid size, but appears to be minimal in large colloids. [Copyright &y& Elsevier]

Background: Antenatal multiple micronutrient (MM) supplementation improves birth outcomes relative to iron-folic acid (IFA) in developing countries, but limited data exist on its impact on pregnancy micronutrient status.Objective: We assessed the efficacy of a daily MM (15 nutrients) compared with IFA supplement, each providing approximately 1 RDA of nutrients and given beginning at pregnancy ascertainment, on late pregnancy micronutrient status of women in rural Bangladesh. Secondarily, we explored other contributors to pregnancy micronutrient status.Methods: Within a double-masked trial (JiVitA-3) among 44,500 pregnant women, micronutrient status indicators were assessed in n = 1526 women, allocated by cluster to receive daily MM (n = 749) or IFA (n = 777), at 10 wk (baseline: before supplementation) and 32 wk (during supplementation) gestation. Efficacy of MM supplementation on micronutrient status indicators at 32 wk was assessed, controlling for baseline status and other covariates (e.g., inflammation and season), in regression models.Results: Baseline status was comparable by intervention. Prevalence of deficiency among all participants was as follows: anemia, 20.6%; iron by ferritin, 4.0%; iron by transferrin receptor, 4.7%; folate, 2.5%; vitamin B-12, 35.4%; vitamin A, 6.7%; vitamin E, 57.7%; vitamin D, 64.0%; zinc, 13.4%; and iodine, 2.6%. At 32 wk gestation, vitamin B-12, A, and D and zinc status indicators were 3.7-13.7% higher, and ferritin, γ-tocopherol, and thyroglobulin indicators were 8.7-16.6% lower, for the MM group compared with the IFA group, with a 15-38% lower prevalence of deficiencies of vitamins B-12, A, and D and zinc (all P < 0.05). However, indicators typically suggested worsening status during pregnancy, even with supplementation, and baseline status or other covariates were more strongly associated with late pregnancy indicators than was MM supplementation.Conclusions: Rural Bangladeshi women commonly entered pregnancy deficient in micronutrients other than iron and folic acid. Supplementation with MM improved micronutrient status, although deficiencies persisted. Preconception supplementation or higher nutrient doses may be warranted to support nutritional demands of pregnancy in undernourished populations. This trial was registered at clinicaltrials.gov as NCT00860470. [ABSTRACT FROM AUTHOR]

Highlights • Electrical impedance myography and quantitative ultrasound are potential biomarkers in Duchenne muscular dystrophy (DMD). • They provide related but complementary information on muscle health. • Their combined use may be more valuable for assessing disease progression in DMD. Abstract Objectives Quantitative ultrasound (QUS), including grayscale level analysis (GLA) and quantitative backscatter analysis (QBA), and electrical impedance myography (EIM) have been proposed as biomarkers in Duchenne muscular dystrophy (DMD). However, the relationship between these methods has not been assessed. Methods QUS values (including GLA and QBA) and several EIM measures were recorded from six muscles in 36 DMD and 29 healthy boys between ages 5 and 13 years at baseline, 6-months, and 12-months. Results In the DMD boys, a moderate correlation was noted between QUS and EIM parameters, with the strongest correlations being identified for averaged muscle values. Of the individual muscles, biceps brachii and deltoid showed the strongest correlations. For example, in biceps, the QBA/EIM correlation coefficient (Spearman rho) was ≥0.70 (p < 0.01). Importantly, changes in QUS values over 12 months also correlated moderately with changes in EIM parameters and EIM/QBA rho values mostly varied between −0.53 and −0.70 (p ≤ 0.02). No significant correlations were identified in the healthy boys. Conclusions A moderate correlation of QUS with EIM in DMD boys suggests that the two technologies provide related data but are sensitive to different pathological features of muscle. Significance The use of both technologies jointly in assessing DMD progression and response to therapy should be considered. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The quadricyclane (QC) ligation is a bioorthogonal reaction between a quadricyclane moiety and a nickel bis(dithiolene) derivative. Here we show that a QC amino acid can be incorporated into a protein site-specifically using the pyrrolysine-based genetic code expansion platform, and subsequently used for ligation chemistry. Additionally, we exploited the photolability of the QC ligation product to render the adduct cleavable with a handheld UV lamp. We further developed a protein purification method that involves QC ligation of biotin to a protein of interest, capture on streptavidin resin, and finally release using only UV light. The QC ligation thus brings novel chemical manipulations to the realm of bioorthogonal chemistry. [ABSTRACT FROM AUTHOR]

Objective To use a standard modeling approach to evaluate the feasibility of imaging healthy and diseased skeletal muscle at the microscopic scale with a novel electrical impedance imaging (EII) needle. Methods We modeled an EII needle containing 16 impedance electrodes arranged circumferentially around the shaft of a non-conductive 19-gauge needle in 4 planes. We then combined the finite element method approach with a reconstruction algorithm to create imaging simulations of the electrical properties of the triceps brachii by localized intramuscular fat (as might be seen in any chronic neuromuscular disease) and by localized edema (as in inflammatory myositis or after direct muscle injury). Results We were able to image a 1 cm radial region of interest with a resolution of 200 µm. Modeling localized deposition of fat and pockets of inflammatory cells, showing clear differences between the two modeled clinical states. Conclusions This modeling study shows needle EII’s ability to image the internal composition of muscle. These results can serve as an initial guide in designing and manufacturing prototype EII needles for experimental testing in animals and eventually in humans. Significance Needle EII could serve as a new minimally invasive technique for imaging human muscle at the microscopic scale, potentially serving as a new biomarker to assess disease response to therapy. [ABSTRACT FROM AUTHOR]

Four-dimensional (4D) printing of multi-directionally reinforced preforms has tremendous potential for the development of next generation functional composites by using the capabilities of 3D printing technology, 3D textile preform design, and polymer shape memory behavior. This work demonstrates the shape memory behavior and recovery force of 4D printed circular braided tube preforms and their silicone elastomer matrix composites. The preforms were printed by fused deposition modeling using the shape memory polymer (SMP), polylactic acid (PLA). The effects of braiding angle, tube wall thickness, and shape recovery temperature on the shape memory behavior of 4D printed tube preforms and their silicone elastomer matrix composites have been characterized. Measurements of shape recovery forces of the preform and composite were conducted using dynamic mechanical analysis (DMA). The braided microstructural parameters and shape recovery temperature have a significant effect on the preform shape memory behavior. The introduction of the silicone elastomer matrix greatly enhances the shape recovery force, shape recovery ratio, as well as radial compressive failure load of the 4D printed preform/silicone elastomer matrix composite. Building on these results, a potential application for 4D printed textile functional composites is presented. [ABSTRACT FROM AUTHOR]

Background Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12 month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. Methods Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. Conclusion This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. Trial registration ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015). [ABSTRACT FROM AUTHOR]

Background: Malnutrition affects body growth, size, and composition of children. Yet, few functional biomarkers are known to be associated with childhood morphology. Objective: This cross-sectional study examined associations of anthropometric indicators of height, musculature, and fat mass with plasma proteins by using proteomics in a population cohort of school-aged Nepalese children. Methods: Height, weight, midupper arm circumference (MUAC), triceps and subscapular skinfolds, upper arm muscle area (AMA), and arm fat area (AFA) were assessed in 500 children 6-8 y of age. Height-for-age z scores (HAZs), weight-forage z scores (WAZs), and body mass index-for-age z scores (BAZs) were derived from the WHO growth reference. Relative protein abundance was quantified by using tandem mass spectrometry. Protein-anthropometry associations were evaluated by linear mixed-effects models and identified as having a false discovery rate (q) <5%. Results: Among 982 proteins, 1, 10, 14, and 17 proteinswere associatedwith BAZ, HAZ,MUAC, and AMA, respectively (q < 0.05). Insulin-like growth factor (IGF)-I, 2 IGF-binding proteins, and carnosinase-1 were associated with both HAZ and AMA. Proteins involved in nutrient transport, activation of innate immunity, and bone mineralization were associated with HAZ. Several extracellular matrix proteins were positively associated with AMA alone. The proteomes of MUAC and AMA substantially overlapped, whereas no proteins were associated with AFA or triceps and subscapular skinfolds. Myosin light-chain kinase, possibly reflecting leakage from muscle, was inversely associated with BAZ. The proteome of WAZ was the largest (n = 33) and most comprehensive, including proteins involved in neural development and oxidative stress response, among others. [ABSTRACT FROM AUTHOR]

Background and purpose To study internal and external generalizability of temporal dose–response relationships for xerostomia after intensity-modulated radiotherapy (IMRT) for head and neck cancer, and to investigate potential amendments of the QUANTEC guidelines. Material and methods Objective xerostomia was assessed in 121 patients (n Cohort1 = 55; n Cohort2 = 66) treated to 70 Gy@2 Gy in 2006–2015. Univariate and multivariate analyses (UVA, MVA with 1000 bootstrap populations) were conducted in Cohort1 , and generalizability of the best-performing MVA model was investigated in Cohort2 (performance: AUC, p -values, and Hosmer–Lemeshow p -values (p HL )). Ultimately and for clinical guidance, minimum mean dose thresholds to the contralateral and the ipsilateral parotid glands (Dmean contra , Dmean ipsi ) were estimated from the generated dose–response curves. Results The observed xerostomia rate was 38%/47% (3 months) and 19%/23% (11–12 months) in Cohort1/Cohort2 . Risk of xerostomia at 3 months increased for higher Dmean contra and Dmean ipsi ( Cohort1 : 0.17·Dmean contra + 0.11·Dmean ipsi -8.13; AUC = 0.90 ± 0.05; p = 0.0002 ± 0.002; p HL = 0.22 ± 0.23; Cohort2 : AUC = 0.81; p < 0.0001; p HL = 0.27). The identified minimum Dmean contra thresholds were lower than in the QUANTEC guidelines ( Cohort1/Cohort2: Dmean contra = 12/19 Gy; Dmean contra , Dmean ipsi = 16, 25/20, 26 Gy). Conclusions Increased Dmean contra and Dmean ipsi explain short-term xerostomia following IMRT. Our results also suggest decreasing Dmean contra to below 20 Gy, while keeping Dmean ipsi to around 25 Gy. Long-term xerostomia was less frequent, and no dose–response relationship was established for this follow-up time. [ABSTRACT FROM AUTHOR]

Introduction Posterior cruciate ligament (PCL) tears are commonly due to motor vehicle accidents or sports-related trauma but can differ geographically. We report the various causes, types, and associated injuries of PCL tears in Taiwan. Methods One hundred forty patients with arthroscopically treated PCL tears were reviewed. Results Scooter-related trauma was the most common cause of PCL tear in our series and is typically an isolated ligamentous injury. High-velocity motor vehicle accidents accounted for a small percentage of PCL tears. Conclusion Scooter-related PCL tears are common in Taiwanese patients and are often isolated ligamentous injuries similar to low-velocity sports-related PCL injuries. [ABSTRACT FROM AUTHOR]

Telehealth facilitates access to cancer care for patients unable to attend in-person consultations, as in COVID-19. This systematic review used the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework to evaluate telehealth implementation and examine enablers and barriers to optimal implementation in oncology. MEDLINE, PubMed, CINAHL, and the Cochrane Database of Systematic Reviews were searched between January 2011-June 2022. Eighty-two articles representing 73 studies were included. One study explicitly used the RE-AIM framework to guide study design, conduct, or reporting. Reach (44%) and implementation (38%) were most commonly reported, maintenance (5%) least commonly. Key telehealth implementation enablers included professional-led delivery, patient-centred approaches, and positive patient perceptions. Key barriers included patient discomfort with technology, limited supporting clinic infrastructure, and poor access to reliable internet connection and videoconferencing. While a patient-centred and professional-supported approach enables telehealth implementation, technology and infrastructure constraints need surmounting for sustained implementation beyond the COVID-19 pandemic. • Telehealth implementation can augment cancer care, as in COVID-19. • More is known about telehealth reach & implementation than adoption & maintenance. • Patient-centredness, professional-led & positive perceptions enable implementation. • Discomfort with technology & limited infrastructure hinder implementation. • Tailored interventions are needed to improve reach for diverse populations. [ABSTRACT FROM AUTHOR]

Over-activation of prefrontal cortex during walking has been reported in older adults versus young adults. Heighted activity in prefrontal cortex suggests a shift toward an executive control strategy to control walking. A potential contributing factor is degraded functioning of pattern-generating locomotor circuits in the central nervous system that are important to walking coordination. Somatosensory information is a crucial input to these circuits, so age-related impairment of somatosensation would be expected to compromise the neural control of walking. The present study tested the hypothesis that poorer somatosensation in the feet of older adults will be associated with greater recruitment of the prefrontal cortex during walking. This study also examines the extent to which somatosensory function and prefrontal activity are associated with performance on walking and balance assessments. Forty seven older adults (age 74.6 ± 6.8 years; 32 female) participated in walking assessments (typical walking and obstacle negotiation) and Berg Balance Test. During walking, prefrontal activity was measured with functional near infrared spectroscopy (fNIRS). Participants also underwent somatosensory testing with Semmes-Weinstein monofilaments. The primary findings is that worse somatosensory monofilament level was associated with greater prefrontal cortical activity during typical walking (r = 0.38, p = 0.008) and obstacle negotiation (r = 0.40, p = 0.006). For the obstacle negotiation task, greater prefrontal activity was associated with faster walking speed (p = 0.004). Poorer somatosensation was associated with slower typical walking speed (p = 0.07) and obstacles walking speed (p < 0.001), as well as poorer balance scores (p = 0.03). The study findings are consistent with a compensation strategy of recruiting prefrontal/executive control resources to overcome loss of somatosensory input to the central nervous system. Future research should further establish the mechanisms by which somatosensory impairments are linked to the neural control and performance of walking tasks, as well as develop intervention approaches. • Somatosensory information is crucial to neural control of walking. • Older adults experience impairments in tactile somatosensation of the feet. • To compensate, older adults may rely on executive control processes during walking. • Results show an association between poor sensation and higher prefrontal activity. • Poor sensation was also associated with poorer walking and balance performance. [ABSTRACT FROM AUTHOR]

• Showed the feasibility of identifying health condition in drivers by monitoring their actions. • Built model of driver behavior through machine learning from observation. • Falconet system employs Neuroevolution and Particle Swarm Optimization to build model. This paper describes our investigation to determine whether undesirable health conditions of an automobile driver can be identified in real time solely by monitoring and assessing his/her driving behavior. The concept has great potential to reduce the accident rate on roadways, especially for young inexperienced drivers who may be suffering from chronic health conditions that when uncontrolled, can result in dangerous driving actions. Our approach involves building models of "normal" and "abnormal" driving by an individual through machine learning from observation (MLfO, or simply LfO). Conceptually, discrepancies between actual driving actions taken by a driver in real time and the actions prescribed by a model of her/his normal driving, and/or similarities to a model of his/her abnormal driving, could indicate a dangerous medical condition. If appropriate, the system could alert the driver and/or the appropriate authorities (e.g., EMTs, police, or parents if a minor) of the potential for danger. More specifically, our research created models of human driving through the use of an LfO system developed previously in our laboratory called Force-feedback Approach to Learning from Coaching and Observation with Natural and Experiential Training (Falconet). Time-stamped traces of actions taken by 12 human test subjects in a driving simulator were collected and used to create the models of human driving behavior through Falconet. Then the overall actions prescribed by the models (called the agents) were compared to the original traces to ascertain whether similarities and/or differences between the human test subject behaviors and the agent behaviors could be indicative of the target conditions. In our use case presented here, the target condition was Attention Deficit/Hyperactivity Disorder (ADHD), a condition that afflicts many driving age teenagers and which can be detrimental to safe driving when not under control through medication. The work described in this paper is exploratory in nature, with the objective of showing scientific feasibility. The results of extensive testing indicate that the agents created with the Falconet system produced promising results, being able to correctly characterize traces in up to nearly 82% of the test cases presented. Nevertheless, as is typical in such exploratory works, we found that much further work remains to be done before this concept becomes ready for commercial application. In this paper we describe the approach taken, the agents created and the extensive quantitative experiments conducted, as well as any insights learned. Areas of further research are also identified and discussed. [ABSTRACT FROM AUTHOR]

Background The mammalian target of rapamycin (mTOR) inhibitor is an immunosuppressive drug used in kidney transplantation. Whether the mTOR inhibitor is associated with reduced risk of cancer development and mortality after kidney transplantation is controversial. Methods We conducted a nationwide population-based study. Patients who did not have malignancy history and received kidney transplantation between 2010 and 2013 were enrolled. Recipients who had mTOR inhibitors (n = 430) for more than 30 days comprised the study group; 1720 recipients who did not have mTOR inhibitors comprised the control group. The primary outcome is the development of cancer after kidney transplantation. These patients were followed until the first-time admission with diagnosis of cancer, death, or the end of 2014. A Cox proportional-hazard model was used to determine the risk of cancer development and all-cause mortality. Results During the 35-month median duration of observation, there were 16 and 61 patients with cancer development in the study group and the control group, respectively. The cancer incidence was 12.8 and 12.4 per 1000 person-years. There were 10 and 135 mortality cases, with the incidence rate of 7.8 and 26.9 per 1000 person-years. After multivariable adjustment, the mTOR inhibitors users were not associated with reduced risk of new cancer development as compared with control (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.46–1.60; P = .63), nor risk of all-cause mortality (HR, 0.70; 95% CI, 0.33–1.46; P = .34). Conclusions The use of mTOR inhibitors was not associated with a reduction in the risk of cancer development and all-cause mortality in kidney transplantation recipients. [ABSTRACT FROM AUTHOR]

Background: The term vitamin E describes a family of 8 vitamers, 1 of which is α-tocopherol, that is essential for human health. Vitamin E status remains largely unknown in low-income countries because of the complexity and cost of measurement. Quantitative proteomics may offer an approach for identifying plasma proteins for assessing vitamin E status in these populations.Objective: To improve options for vitamin E status assessment, we sought to detect and quantify a set of plasma proteins associated with α- and γ-tocopherol concentrations in a cohort of 500 rural Nepalese children aged 6-8 y and, based on nutrient-protein associations, to predict the prevalence of vitamin E deficiency (α-tocopherol <12 μmol/L).Methods: Study children were born to mothers enrolled in an earlier antenatal micronutrient trial in Sarlahi District, Nepal. Plasma α- and γ-tocopherol concentrations were measured by high-performance liquid chromatography. Plasma aliquots were depleted of 6 high-abundance proteins, digested with trypsin, labeled with isobaric mass tags, and assessed for relative protein abundance by tandem mass spectrometry. Linear mixed-effects models were used to evaluate the association between α-tocopherol status and relative protein abundance and to predict deficiency.Results: We quantified 982 plasma proteins in >10% of all child samples, of which 119 correlated with α-tocopherol (false discovery rate, q < 0.10). Proteins were primarily involved in lipid transport, coagulation, repair, innate host defenses, neural function, and homeostasis. Six proteins [apolipoprotein (apo)C-III; apoB; pyruvate kinase, muscle; forkhead box 04; unc5 homolog C; and regulator of G-protein signaling 8] explained 71% of the variability in plasma α-tocopherol, predicting an in-sample population prevalence of vitamin E deficiency of 51.4% (95% CI: 46.4%, 56.3%) compared with a measured prevalence of 54.8%. Plasma γ-tocopherol was associated with 12 proteins (q < 0.10), 2 of which (apoC-III and Misato 1) explained 20% of its variability.Conclusions: In this undernourished population of children in South Asia, quantitative proteomics identified a large plasma α-tocopherome from which 6 proteins predicted the prevalence of vitamin E deficiency. The findings illustrate that protein biomarkers, once absolutely quantified, can potentially predict micronutrient deficiencies in populations. The maternal micronutrient supplementation trial from which data were derived as a follow-up activity was registered with clinicaltrials.gov as NCT00115271. [ABSTRACT FROM AUTHOR]

Background: Pain flare occurs after palliative radiotherapy, and dexamethasone has shown potential for prevention of such flare. We aimed to compare the efficacy of dexamethasone with that of placebo in terms of reduction of incidence of pain flare.Methods: In this double-blind, randomised, placebo-controlled phase 3 trial, patients from 23 Canadian centres were randomly allocated (1:1) with a web-based system and minimisation algorithm to receive either two 4 mg dexamethasone tablets or two placebo tablets taken orally at least 1 h before the start of radiation treatment (a single 8 Gy dose to bone metastases; day 0) and then every day for 4 days after radiotherapy (days 1-4). Patients were eligible if they had a non-haematological malignancy and bone metastasis (or metastases) corresponding to the clinically painful area or areas. Patients reported their worst pain scores and opioid analgesic intake before treatment and daily for 10 days after radiation treatment. They completed the European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C15-PAL, the bone metastases module (EORTC QLQ-BM22), and the Dexamethasone Symptom Questionnaire at baseline, and at days 10 and 42 after radiation treatment. Pain flare was defined as at least a two-point increase on a scale of 0-10 in the worst pain score with no decrease in analgesic intake, or a 25% or greater increase in analgesic intake with no decrease in the worst pain score from days 0-10, followed by a return to baseline levels or below. Primary analysis of incidence of pain flare was by intention-to-treat (patients with missing primary data were classified as having pain flare). This study is registered with ClinicalTrials.gov, number NCT01248585, and is completed.Findings: Between May 30, 2011, and Dec 11, 2014, 298 patients were enrolled. 39 (26%) of 148 patients randomly allocated to the dexamethasone group and 53 (35%) of 150 patients in the placebo group had a pain flare (difference 8·9%, lower 95% confidence bound 0·0, one-sided p=0·05). Two grade 3 and one grade 4 biochemical hyperglycaemic events occurred in the dexamethasone group (without known clinical effects) compared with none in the placebo group. The most common adverse events were bone pain (61 [41%] of 147 vs 68 [48%] of 143), fatigue (58 [39%] of 147 vs 49 [34%] of 143), constipation (47 [32%] of 147 vs 37 [26%] of 143), and nausea (34 [23%] of 147 vs 34 [24%] of 143), most of which were mild grade 1 or 2.Interpretation: Dexamethasone reduces radiation-induced pain flare in the treatment of painful bone metastases.Funding: The NCIC CTG's programmatic grant from the Canadian Cancer Society Research Institute. [ABSTRACT FROM AUTHOR]

Background context Choosing the best surgical treatment for patients with spinal metastases remains a significant challenge for spine surgeons. There is currently no gold standard for surgical treatments. The Aarhus Spinal Metastases Algorithm (ASMA) was established to help surgeons choose the most appropriate surgical intervention for patients with spinal metastases. Purpose The purpose of this study was to evaluate the clinical outcome of stratified surgical interventions based on the ASMA, which combines life expectancy and the anatomical classification of patients with spinal metastases to inform surgical decision making. Study design/Setting This is a retrospective study based on a prospective database. Patient sample A consecutive series of 515 spinal metastatic patients who underwent surgically treatment from December 1992 to June 2012 in Aarhus University Hospital were included prospectively and analyzed in detail retrospectively. Outcome measures Survival time after surgery was determined for all patients. Neurological function was assessed using the Frankel score preoperatively and postoperatively (at the time of discharge). Complete outcome data were retrieved in 97.5% of this cohort. Methods Patients with spinal metastases were identified from an institutional database that prospectively collected data since 1992. Survival status data were obtained from a national registry. Neurological function was determined from the same institutional database or local Electronic Patient Journal system. Surgeons evaluated and classified patients into five surgical groups preoperatively by using the revised Tokuhashi score (TS) and the Tomita anatomical classification (TC). Results The overall median survival time of the cohort was 6.8 (95% confidence interval: 6.1–7.9) months. The median survival times in the five surgical groups determined by the ASMA were 2.1 (TS 0–4, TC 1–7), 5.1 (TS 5–8, TC 1–7), 12.1 (TS 9–11, TC 1–7 or TS 12–15, TC 7), 26.0 (TS 12–15, TC 4–6), and 36.0 (TS 12–15, TC 1–3) months. The 30-day mortality rate was 7.5%. Postoperative neurological function was maintained or improved in 469 patients (92.3%). Overall reoperation rate was 13.5%, commonly because of postoperative hematoma and new limb weakness. Conclusions The ASMA recommends at least two surgical options for a particular patient by determining the preoperative life expectancy and anatomical classification of the spinal metastases. This algorithm could help spine surgeons to discriminate the risks of surgeries. The ASMA provides a tool to guild surgeons to evaluate the spinal metastases patients, select potential optimal surgery, and avoid life-threatening risks. [ABSTRACT FROM AUTHOR]

As the U.S. population ages, efficacious interventions are needed to manage pain and maintain physical function among older adults with osteoarthritis (OA). Skeletal muscle weakness is a primary contributory factor to pain and functional decline among persons with OA, thus interventions are needed that improve muscle strength. High-load resistance exercise is the best-known method of improving muscle strength; however high-compressive loads commonly induce significant joint pain among persons with OA. Thus interventions with low-compressive loads are needed which improve muscle strength while limiting joint stress. This study is investigating the potential of an innovative training paradigm, known as Kaatsu, for this purpose. Kaatsu involves performing low-load exercise while externally-applied compression partially restricts blood flow to the active skeletal muscle. The objective of this randomized, single-masked pilot trial is to evaluate the efficacy and feasibility of chronic Kaatsu training for improving skeletal muscle strength and physical function among older adults. Participants aged ≥ 60 years with physical limitations and symptomatic knee OA will be randomly assigned to engage in a 3-month intervention of either (1) center-based, moderate-load resistance training, or (2) Kaatsu training matched for overall workload. Study dependent outcomes include the change in 1) knee extensor strength, 2) objective measures of physical function, and 3) subjective measures of physical function and pain. This study will provide novel information regarding the therapeutic potential of Kaatsu training while also informing about the long-term clinical viability of the paradigm by evaluating participant safety, discomfort, and willingness to continually engage in the intervention. [ABSTRACT FROM AUTHOR]

Background: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. Patients and methods: Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m² i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. Results: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75--1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52--1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P=1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. Conclusion: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRASmutant- positive NSCLC. [ABSTRACT FROM AUTHOR]

Mammalian cells are able to sense environmental oxidative and genotoxic conditions such as the environmental low-dose ionizing radiation (LDIR) present naturally on the earth’s surface. The stressed cells then can induce a so-called radioadaptive response with an enhanced cellular homeostasis and repair capacity against subsequent similar genotoxic conditions such as a high dose radiation. Manganese superoxide dismutase (MnSOD), a primary mitochondrial antioxidant in mammals, has long been known to play a crucial role in radioadaptive protection by detoxifying O 2 •− generated by mitochondrial oxidative phosphorylation. In contrast to the well-studied mechanisms of SOD2 gene regulation, the mechanisms underlying posttranslational regulation of MnSOD for radioprotection remain to be defined. Herein, we demonstrate that cyclin D1/cyclin-dependent kinase 4 (CDK4) serves as the messenger to deliver the stress signal to mitochondria to boost mitochondrial homeostasis in human skin keratinocytes under LDIR-adaptive radioprotection. Cyclin D1/CDK4 relocates to mitochondria at the same time as MnSOD enzymatic activation peaks without significant changes in total MnSOD protein level. The mitochondrial-localized CDK4 directly phosphorylates MnSOD at serine-106 (S106), causing enhanced MnSOD enzymatic activity and mitochondrial respiration. Expression of mitochondria-targeted dominant negative CDK4 or the MnSOD-S106 mutant reverses LDIR-induced mitochondrial enhancement and adaptive protection. The CDK4-mediated MnSOD activation and mitochondrial metabolism boost are also detected in skin tissues of mice receiving in vivo whole-body LDIR. These results demonstrate a unique CDK4-mediated mitochondrial communication that allows cells to sense environmental genotoxic stress and boost mitochondrial homeostasis by enhancing phosphorylation and activation of MnSOD. [ABSTRACT FROM AUTHOR]

Aflatoxin B 1 is a potent carcinogen, occurring from mold growth that contaminates staple grains in hot, humid environments. In this investigation, aflatoxin B 1 -lysine albumin biomarkers were measured by mass spectrometry in rural South Asian women, during the first and third trimester of pregnancy, and their children at birth and at two years of age. These subjects participated in randomized community trials of antenatal micronutrient supplementation in Sarlahi District, southern Nepal and Gaibandha District in northwestern Bangladesh. Findings from the Nepal samples demonstrated exposure to aflatoxin, with 94% detectable samples ranging from 0.45 to 2939.30 pg aflatoxin B 1 -lysine/mg albumin during pregnancy. In the Bangladesh samples the range was 1.56 to 63.22 pg aflatoxin B 1 -lysine/mg albumin in the first trimester, 3.37 to 72.8 pg aflatoxin B 1 -lysine/mg albumin in the third trimester, 4.62 to 76.69 pg aflatoxin B 1 -lysine/mg albumin at birth and 3.88 to 81.44 pg aflatoxin B 1 -lysine/mg albumin at age two years. Aflatoxin B 1 -lysine adducts in cord blood samples demonstrated that the fetus had the capacity to convert aflatoxin into toxicologically active compounds and the detection in the same 2-year-old children illustrates exposure over the first 1000 days of life. [ABSTRACT FROM AUTHOR]

Abstract: Age-related impairment of neuromuscular activation has been shown to contribute to weakness in older adults. However, it is unclear to what extent impaired neuromuscular activation independently accounts for decline of mobility function. The hypothesis of this study is that the capability to produce rapid neuromuscular activation during maximal effort leg muscle contractions will be shown to be an independent predictor of mobility function in older men and women after accounting for muscle size and adiposity, body composition and age. Twenty six older men and eighteen older women (aged 70–85years) participated in this study. Mobility function was assessed by the 400-m walk test. Neuromuscular activation of the quadriceps muscle group was assessed by surface electromyography (“rate of EMG rise”). Thigh muscle cross sectional area and adiposity were assessed by computed tomography. In males, univariate regression analysis revealed strong associations between walking speed and a number of predictors including age (p <0.01), muscle area (p <0.01), intermuscular adipose tissue area (p <0.01), and rate of EMG rise (p <0.001). Subsequent multiple regression analysis with all variables accounted for 72% of the variability in walking speed (p <.0001), with age and rate of EMG rise as the dominant variables in the model. In females, univariate analysis showed a significant association only between walking speed and subcutaneous adipose tissue area (p <0.05). Multiple regression analysis accounted for only 44% of the variability in walking speed, and was not statistically significant (p =0.18). The present findings indicate that the capability to rapidly activate the quadriceps muscle group is an important factor accounting for inter-individual variability of walking speed among older men, but not among older women. This research is important for informing the design of assessments and interventions that seek to detect and prevent impairments that contribute to age-related mobility disability. [Copyright &y& Elsevier]

Abstract: Background: Electrical impedance myography and quantitative ultrasound are two noninvasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy. However, their comparative sensitivity to disease status and how they relate to one another are unknown. Methods: We performed a cross-sectional analysis of electrical impedance myography and quantitative ultrasound in 24 healthy boys and 24 with Duchenne muscular dystrophy, aged 2 to 14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child, and the data averaged for each individual. Results: Both electrical impedance myography and quantitative ultrasound differentiated healthy boys from those with Duchenne muscular dystrophy (P < 0.001 for both). Quantitative ultrasound values correlated with age in Duchenne muscular dystrophy boys (rho = 0.45; P = 0.029), whereas electrical impedance myography did not (rho = −0.31; P = 0.14). However, electrical impedance myography phase correlated with age in healthy boys (rho = 0.51; P = 0.012), whereas quantitative ultrasound did not (rho = −0.021; P = 0.92). In Duchenne muscular dystrophy boys, electrical impedance myography phase correlated with the North Star Ambulatory Assessment (rho = 0.65; P = 0.022); quantitative ultrasound revealed a near-significant association (rho = −0.56; P = 0.060). The two technologies trended toward a moderate correlation with one another in the Duchenne muscular dystrophy cohort but not in the healthy group (rho = −0.40; P = 0.054 and rho = −0.32; P = 0.13, respectively). Conclusions: Electrical impedance myography and quantitative ultrasound are complementary modalities for the assessment of boys with Duchenne muscular dystrophy; further study and application of these two modalities alone or in combination in a longitudinal fashion are warranted. [Copyright &y& Elsevier]

We report the first quality-of-life assessment of a MEK inhibitor in metastatic melanoma from a phase III study. Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Less functional impairment, smaller declines in health status, and less exacerbation of symptoms were observed with trametinib.Background In a randomized phase III study, trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Patients and methods Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. Results In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4–5 points with chemotherapy but improved by 2–3 points with trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8–11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4–8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for trametinib decreased from baseline (symptoms improved) for pain (11–12 points), insomnia (10–12 points), and appetite loss (1–5 points), whereas those for diarrhea worsened (15–16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent. Conclusions This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy. [ABSTRACT FROM PUBLISHER]

Summary: Background: Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. Methods: We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. Findings: Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85–2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73–17·15; p=0·094). Interpretation: In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. Funding: Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris. [ABSTRACT FROM AUTHOR]

Background Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. Methods Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. Results A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02–1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. Conclusions Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients. [ABSTRACT FROM PUBLISHER]

Abstract: Background: The clinical application of porcine-derived xenotransplants is limited by the potential risk of infection due to the presence of porcine endogenous retrovirus (PERV) in tissues, organs, and cells. The establishment of pig fibroblasts with low PERV expression and without PERV-C can provide a nuclear donor to generate a safer transgenic pig. Methods: In this study, we obtained Chinese Experimental Miniature Pig fibroblasts (CEMPF) with low expression of PERV and none of PERV-C. We designed small interfering RNA (siRNA) expressed as short hairpin RNAs (shRNA) based on the highly conserved gag and pol regions of PERV and screened for the most effective siRNA to inhibit PERV expression. The selected shRNA-pol3 fragment was introduced into the CEMPF to obtain an engineered CEMPF stably expressing shRNA-pol3. Results: The PERV mRNA expression level in the engineered CEMPF was only 7.9% of that observed in fibroblasts from wild-type CEMPF, PERV P15E protein expression was significantly reduced. HEK293 cells cocultured with the supernate of the engineered CEMPF showed no PERV infection. Conclusions: Engineered CEMPF, which possess no risk of PERV-A/C infection, can serve as a nuclear donor to generate xenograft donor pigs. [Copyright &y& Elsevier]

Abstract: Objectives: To compare subthalamic nucleus (STN) to globus pallidus internus (GPi) deep brain stimulation (DBS) for control of motor fluctuations and for potential dyskinesia-suppressing qualities. Methods: We conducted a retrospective database review of all patients who underwent GPi or STN DBS for idiopathic Parkinson''s disease. Direct dyskinesia suppression (dDS) was defined as improvement in dyskinesia subscore of the Unified Parkinson''s Disease Rating Scale (UPDRS) part IV (items 32–34), despite lack of reduction in dopaminergic medication dosage. We analyzed the data using methods appropriate for a case–control study. Results: A total of 133 patients were evaluated. At the last evaluation Dyskinesia scores and motor fluctuations significantly improved in both the GPi (p < 0.0001) and STN groups (p < 0.0001). The GPi group was more likely than the STN group to experience dDS (odds ratio = 1.95, 95% CI = 0.556, 3.21). However, the association between DBS target and dDS was not statistically significant (Pearson chi-square = 2.286, p = 0.131). Conclusions: The overall clinical outcome of STN and GPi DBS for control of dyskinesia and motor fluctuations was similar. STN and GPi DBS both had some direct dyskinesia suppression effects. [Copyright &y& Elsevier]

Aim: To present the neuroradiological and clinical findings of fourth-ventricular meningiomas to increase awareness of this entity. Materials and methods: The computed tomography (CT; n =5), magnetic resonance imaging (MRI; n =9) features and clinical presentations of 10 patients with pathologically documented fourth-ventricular meningiomas were retrospectively analysed. Results: All tumours appeared as well-demarcated masses in the fourth ventricle at CT and MRI. The tumour shape was round in eight cases (80%) and irregular in two cases (20%). The CT images of five cases showed predominantly isoattenuation in three cases and high attenuation in two cases, with a mean attenuation value of 52HU. In addition, calcifications were seen in three cases. At MRI, nine masses were isointense (n =6) or hypointense (n =3) to grey matter on T1-weighted images and mildly hyperintense (n =4), isointense (n =3), hypointense (n =1), and of mixed signal intensity (n =1) on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. Signal voids were visible in two cases. Enhancement after injection of contrast material was marked homogeneous (n =5) or heterogeneous (n =5) on CT or T1-weighted images. Three tumours had mild peritumoural oedema. Three tumours were associated with obstructive hydrocephalus. The pathological subtype of the 10 meningiomas was fibromatous (n =5), atypical (n =2), and one each of transitional, psammomatous, and clear-cell type. Conclusion: Although fourth-ventricular meningioma is quite rare, it should be considered in differential diagnosis of neoplasms within the fourth ventricle. The relatively typical radiological appearance, combined the age and sex of patients, can suggest the diagnosis of fourth-ventricular meningioma. [Copyright &y& Elsevier]