Search

Summary Objectives A whole body vibration platform using vertical oscillation has been shown to be efficacious in reducing vocal fatigue in adults. This study aimed to investigate whether this platform-generated whole body vibration was unique in reducing vocal fatigue by comparing it with self-generated whole body vibration. Methods Twenty-four female adults (mean age = 23.96 years) were randomly assigned to one of the following three groups: a machine-generated whole body vibration group (N = 8), a self-generated whole body vibration group (N = 8), and a placebo vocal resting group (N = 8). All participants performed a karaoke singing task for at least 95 minutes. Each participant received 10 minutes of platform-generated vibration, self-vibration, or sham localised vibration (placebo group with basically voice rest only), according to their group allocation. Vocal function ability, measured by the highest fundamental frequency produced, and a self-reported vocal fatigue score were evaluated at three time points: baseline (prefatigue), after the singing task (post-fatigue) and post-vibration. Results The study revealed that machine-generated whole body vibration was significantly better at improving vocal fatigue than self-generated whole body vibration or voice rest. Conclusion The findings support previous research that machine-generated whole body vibration is effective in reducing vocal fatigue. The non-significant results of self-generated whole body vibration in terms of relieving vocal fatigue suggest that inadequate vibration frequency or amplitude together with leg muscle fatigue may have been the main factor of ineffectiveness.

Stress has a detrimental impact on memory, the hippocampus, and psychological health. Psychopathology research on stress has centered mainly on psychiatric diagnoses rather than symptom dimensions, and less attention has been given to the neurobiological factors through which stress might be translated into psychopathology. The present work investigates the transdiagnostic relationship of cumulative stress with episodic memory and the hippocampus (both structure and function) and explores the extent to which stress mediates the relationship between personality psychopathology and hippocampal size and activation. Cumulative lifetime stress was assessed in a sample of females recruited to vary in stress exposure and severity of personality psychopathology. Fifty-six participants completed subjective and objective tests of episodic memory, a T2-weighted high-resolution magnetic resonance imaging (MRI) scan of the medial-temporal lobe, and functional MRI (fMRI) scanning during a learning and recognition memory task. Higher cumulative stress was significantly related to memory complaints (but not episodic memory performance), lower bilateral hippocampal volume, and greater encoding-related hippocampal activation during the presentation of novel stimuli. Furthermore, cumulative stress significantly mediated the relationship between personality psychopathology and both hippocampal volume and activation, whereas alternative mediation models were not supported. The findings suggest that structural and functional activation differences in the hippocampus observed in case-control studies of psychiatric diagnoses may share cumulative stress as a common factor, which may mediate broadly reported relationships between psychopathology and hippocampal structure and function.

––The Gobi-Altai, Mongolia, includes high mountain ranges that have accommodated the compressional stresses derived from the collision between the Eurasian and Indian Plates. The Gurvan Bogd, which is one of the main mountain ranges in the Gobi-Altai, is a restraining bend along the Bogd sinistral fault. Although surface ruptures did not form near the Artz Bogd during the Mw = 8.1 Gobi-Altai earthquake of 1957, it is still active, as evidenced by a growing topography (i.e., forebergs). Six foreberg ridges have formed in the foreland of the Artz Bogd, which are considered to be the result of surface deformation of alluvial fans due to thrusting. One stream has cut down to expose a foreberg tip, providing the opportunity to explore the slip evolution of the region. Here we map a growing fault structure related to blind thrusting. We identify five faulting events from an analysis of the outcrop and apply optically stimulated luminescence dating to the faulted sedimentary layers, yielding an average slip rate of 0.045 ± 0.007 m/kyr and an earthquake recurrence interval of 5.8 ± 0.5 kyr over the last ~32 kyr. Furthermore, the long-term (~600 kyr) uplift rate of the foreberg is 0.067 ± 0.007 m/kyr, as deduced by dividing the vertical displacement of the alluvial fan surface by the 10Be surface exposure ages of boulders on the fan. The discrepancy (20–30%) between these two deformation rates may be due to the different timescales they cover and an along-strike gradient in slip rate.

N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.

Blockade of the binding between neonatal Fc receptor and IgG‐Fc reduces circulating IgG, and thus emerges as a potential therapy for IgG‐mediated autoimmune conditions. This was a double blind, randomized, single ascending dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of HBM9161 (a fully humanized Fc receptor monoclonal antibody) in healthy Chinese volunteers. Subjects were randomized to receive a single s.c. dose of HBM9161 or placebo in a 3:1 ratio in 3 dosing cohorts (340 mg, 510 mg, or 680 mg, respectively), and then followed up for 85 days. Study end points included incidence of adverse event (AE), serum drug concentration, IgG and its subclasses, and anti‐drug antibodies (ADAs). Twenty‐four subjects were randomized. Dose‐dependent reduction of total IgG occurred rapidly from baseline to reach nadir at day 11, then recovered steadily from day 11 to day 85. The mean maximum percentage reductions from baseline total IgG were 21.0 ± 9.3%, 39.8 ± 5.13%, and 41.2 ± 10.4% for subjects receiving HBM9161 340 mg, 510 mg, and 680 mg, respectively. The exposure of HBM9161 (areas under the curve [AUCs] and peak plasma concentration [Cmax]) increased in a more than dose‐proportional manner at the dose examined. All reported AEs were mild in severity. The most reported AEs in the HBM9161 groups were influenza‐like illness and rash. Two subjects developed ADA during the study period. A single s.c. dose of HBM9161 results in sustained and dose‐dependent IgG reduction, and was well‐tolerated at a dose up to 680 mg in Chinese subjects. The data warrant further investigation of its effects in IgG‐mediated autoimmune disorders.

The demand for enteral tube feeding in children is increasing globally. As our ability to manage complex medical conditions improves, so too does our understanding of the benefits of good enteral nutrition on health outcomes for these children. If oral feeding is not possible, an enteral tube can provide a viable alternative by delivering nutrition directly into the stomach or jejunum. The decision to recommend a child for long term tube feeding is complex and needs to be balanced against the potential risks. It is therefore essential that healthcare professionals keep up to date with the indications for referral, understand the current options available to children, and are able to identify common and serious problems that can arise following tube insertion. Healthcare professionals should also be aware of the debate surrounding the administration of blended feeds via the enteral tube. While some children may benefit from this practice, there are important considerations to be made for children receiving home blended feeds versus enteral formula. In this article, we review the indications for enteral tube insertion, device selection, complications and subsequent management. In addition, we review the logistics and implications for families and healthcare teams aiming to start blended tube feeding.

Nickel, the fifth most common element on Earth, is the leading inducer of contact allergies in humans, with potent immunological effects. Nickel-induced contact allergies predominantly affect females. Maternal exposure to nickel has been associated with several developmental abnormalities. However, how a maternal nickel exposure affects the development of atopic diathesis and immune abnormalities in children has never been addressed.We aimed to determine whether maternal nickel exposure affects the development of atopic dermatitis and immune abnormalities in their children.Using a birth cohort study, we analysed 140 mother-child pairs recruited in 2012-2015 from central Taiwan. Maternal exposure to nickel was estimated using urinary nickel levels measured by inductively coupled plasma mass spectrometry (ICP-MS). The serum levels of 65 analytes and IgE in 3-year-old children were profiled with a multiplex ELISA. The correlation between the maternal urinary nickel concentration and serum analyte levels was assessed using Spearmen's correlation. Multivariant regression analysis was performed to evaluate the association between maternal urinary nickel levels and serum analyte concentrations in their children.The geometric means of the maternal urinary nickel and the children's serum IgE levels were 2.27 μg/L and 69.71 IU/mL, respectively. The maternal nickel exposure was associated with increased serum levels of IL-1β, IL-2, TNF-α, and leukaemia inhibitory factor (LIF) but with decreased serum levels of matrix metalloproteinase-1 (MMP-1), IL-2R, and eotaxin-1 in the children. In addition, the development of childhood atopic dermatitis at 3 years old was significantly associated with the child's serum levels of IgE and IL-2R, but it was negatively associated with the maternal nickel exposure.This is the first study showing the potential immunological effects of maternal nickel exposure in their children at an early developmental stage.

BACKGROUND: It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF). OBJECTIVE: To compare the risk for osteoporotic fracture between anticoagulants. DESIGN: Population-based cohort study. SETTING: Territory-wide electronic health record database of the Hong Kong Hospital Authority. PARTICIPANTS: Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018. MEASUREMENTS: Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs). RESULTS: There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]). LIMITATION: Residual confounding is possible. CONCLUSION: Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants. PRIMARY FUNDING SOURCE: The University of Hong Kong and University College London Strategic Partnership Fund.

AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 μM, CC50 > 25 μM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 μM to 1.92 μM). AB-506 demonstrated activity across HBV genotypes A-H and maintains antiviral activity against nucleos(t)ide analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.

The effect of Si addition on the initial deformation mechanism of Fe–30Mn–9Al–0.9C–0.5Mo cast lightweight steel has been investigated. Atomic-scale analysis by three-dimensional atom-probe tomography confirmed that Si addition accelerates the formation kinetics of the κ-carbide, and increases remarkably the partitioning coefficient of carbon by more than 2 times. Promotion of C partitioning into κ-carbides by Si addition leads to deformation localization in an aged state. This is attributed not only to the increase of the κ-carbide size associated with higher coherency strain, but also to higher frequency of Al-C bonding formation. First-principles calculations indicated that the energy required for a/2 shearing of κ-carbide in the aged 1%-Si steel is higher (561 mJ/m2) than that in the aged Si-free steel (494 mJ/m2). Therefore, Si addition leads to a significant energy difference for shearing and results in different shear bands formation. The operative deformation mechanism can be calculated for this alloy system as a function of precipitates volume fraction and size. It was determined that deformation proceeds primarily by κ-carbide shearing as long as the radius of κ-carbides is smaller than 13.4 nm.

Precision locknuts are widely used in rotary machinery especially the machine tools operating in high speed with high precision. The flank-locking locknut studied in this paper is mainly employed in spindle and ball screw assemblies of machine tools to secure the preloading in the bearings required for better structural stiffness. In service the locknuts often suffer corrosion from the harsh machining environment. The possible effects of corrosion on the surface morphology of locknut, such as flatness and roughness, and its performance were investigated. The locknut was submerged in a 5% NaCl solution following ASTM B895 standard for different durations- 1, 2, and 4 h to speed up the possible corrosion. The treated locknut was then undergone assembling test following ISO 2320 standard. The flatness and roughness on the end face and threads were measured along with microscopic examination. It was found that with increasing duration of corrosion, the surface flatness and roughness became worse. However, the tightening constant of the locknut showed a positive correlation with the increased surface roughness raised by the corrosion treatment.

The AMoRE collaboration is preparing for the second phase of the experiment, AMoRE-II, which will exploit a 100 kg of 100Mo isotopes to search for neutrinoless double beta decay from the isotope. Most of the 100Mo isotopes will be contained in the lithium molybdate (Li2MoO4) crystals, which will act as absorbers of cryogenic calorimeters coupled to MMC (metallic magnetic calorimeter) sensors. The detector array will have a total mass of approximately 200 kg with hundreds of detector modules. Hence, considerable effort has been taken to optimize the lithium molybdate crystal detector in terms of the detector performance and preparation procedure to build many detector modules in a reasonable schedule without compromising the detector performance. We found some critical experimental conditions to improve the energy resolution in a series of test experiments. In this paper, we discuss the effect of surface treatment and thermal link connection in improving the energy resolution from 14–15 keV to below 7 keV at 2.615 MeV, 208Tl gamma line, which is near the Q-value of the decay of 100Mo, 3.034MeV. We also report the high discrimination power for the separation of alpha particles using the simultaneous scintillation light detection with a test performed in the cryogen-free dilution refrigerator.