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Background: Hereditary transthyretin-mediated (hATTR) amyloidosis a hereditary, multi-systemic and life-threatening disease resulting in neuropathy and cardiomyopathy. In the APOLLO study, patisiran, an investigational RNAi therapeutic targeting hepatic TTR production resulted in significant improvement in neuropathy and QoL compared to placebo and was generally well tolerated. Methods: APOLLO, a Phase 3 study of patisiran vs. placebo (NCT01960348) prespecified a cardiac subpopulation (n=126 of 225 total) that included patients with baseline left ventricular (LV) wall thickness ≥ 13mm and no medical history of aortic valve disease or hypertension. Cardiac measures included structure and function by electrocardiography, changes in NT-proBNP and 10-MWT gait speed. Results: At 18 months, patisiran treatment resulted in a mean reduction in LV wall thickness of 1 mm (p=0.017) compared to baseline, which was associated with significant improvements relative to placebo in LV end diastolic volume (+8.31 mL, p=0.036), global longitudinal strain (-1.37%, p=0.015) and NT-proBNP (55% reduction, p=7.7 x 10-8) (Figure 1). Gait speed was also improved relative to placebo (+0.35 m/sec, p=7.4 x 10-9). Rate of death or hospitalization was lower with patisiran. mNIS+7 results in the cardiac subpopulation will also be presented. Conclusions: These data suggest patisiran has the potential to halt or reverse cardiac manifestations of hATTR amyloidosis.
The World Health Organization recently reported that maternal mental health is a major public health concern. As many as one in four women suffer from psychiatric disorders at some point during pregnancy or the first postpartum year. Furthermore, self-injurious thoughts and behaviors (SITBs) represent one of the leading causes of death among women during this time. Thus, efforts to identify women at risk for serious forms of psychopathology and especially for SITBs are of utmost importance. Despite this urgency, current single-diagnostic approaches fail to recognize a significant subset of women who are vulnerable to perinatal stress and distress. The current study was among the first to investigate emotion dysregulation—a multilevel, transdiagnostic risk factor for psychopathology—and its associations with stress, distress, and SITBs in a sample of pregnant women (26–40 weeks gestation) recruited to reflect a range of emotion dysregulation. Both self-reported emotion dysregulation and respiratory sinus arrhythmia, a biomarker of emotion dysregulation, demonstrated expected associations with measures of mental health, including depression, anxiety, borderline personality pathology, and SITBs. In addition, self-reported emotion dysregulation was associated with blunted respiratory sinus arrhythmia responsivity to an ecologically valid infant cry task. Findings add to the literature considering transdiagnostic risk during pregnancy using a multiple-levels-of-analysis approach.
During the summer of 2016, the Hawaii Department of Health responded to the second-largest domestic foodborne hepatitis A virus (HAV) outbreak in the post-vaccine era. The epidemiological investigation included case finding and investigation, sequencing of RNA positive clinical specimens, product trace-back and virologic testing and sequencing of HAV RNA from the product. Additionally, an online survey open to all Hawaii residents was conducted to estimate baseline commercial food consumption. We identified 292 confirmed HAV cases, of whom 11 (4%) were possible secondary cases. Seventy-four (25%) were hospitalised and there were two deaths. Among all cases, 94% reported eating at Oahu or Kauai Island branches of Restaurant Chain A, with 86% of those cases reporting raw scallop consumption. In contrast, a food consumption survey conducted during the outbreak indicated 25% of Oahu residents patronised Restaurant Chain A in the 7 weeks before the survey. Product trace-back revealed a single distributor that supplied scallops imported from the Philippines to Restaurant Chain A. Recovery, amplification and sequence comparison of HAV recovered from scallops revealed viral sequences matching those from case-patients. Removal of product from implicated restaurants and vaccination of those potentially exposed led to the cessation of the outbreak. This outbreak further highlights the need for improved imported food safety.
The main goal of this paper is to provide insights into swash flow dynamics, generated by a non-breaking solitary wave on a steep slope. Both laboratory experiments and numerical simulations are conducted to investigate the details of runup and rundown processes. Special attention is given to the evolution of the bottom boundary layer over the slope in terms of flow separation, vortex formation and the development of a hydraulic jump during the rundown phase. Laboratory experiments were performed to measure the flow velocity fields by means of high-speed particle image velocimetry (HSPIV). Detailed pathline patterns of the swash flows and free-surface profiles were also visualized. Highly resolved computational fluid dynamics (CFD) simulations were carried out. Numerical results are compared with laboratory measurements with a focus on the velocities inside the boundary layer. The overall agreement is excellent during the initial stage of the runup process. However, discrepancies in the model/data comparison grow as time advances because the numerical model does not simulate the shoreline dynamics accurately. Introducing small temporal and spatial shifts in the comparison yields adequate agreement during the entire rundown process. Highly resolved numerical solutions are used to study physical variables that are not measured in laboratory experiments (e.g. pressure field and bottom shear stress). It is shown that the main mechanism for vortex shedding is correlated with the large pressure gradient along the slope as the rundown flow transitions from supercritical to subcritical, under the developing hydraulic jump. Furthermore, the bottom shear stress analysis indicates that the largest values occur at the shoreline and that the relatively large bottom shear stress also takes place within the supercritical flow region, being associated with the backwash vortex system rather than the plunging wave. It is clearly demonstrated that the combination of laboratory observations and numerical simulations have indeed provided significant insights into the swash flow processes.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
The study investigated whether different dietary energy and protein sources affect laying performance, antioxidant status, fresh yolk fatty acid profile and quality of salted yolks in laying ducks. In all, 360 19-week-old Longyan ducks were randomly assigned to four diets in a factorial arrangement (2×2). The four diets consisted of two energy sources, corn (CO) or sorghum (SO) and two protein sources, soybean meal (SM) and rapeseed meal with corn distillers dried grains with solubles (RMD), and each treatment contained six replicates of 15 birds each. The experimental diets were isocaloric (metabolizable energy, 10.84 MJ/kg) and isonitrogenous (CP, 17%). The results showed that egg production, average egg weight, egg mass and feed conversion ratio were not affected by diets (P>0.05). Plasma contents of reduced glutathione (GSH), GSH/oxidized glutathione and total antioxidant capacity were lower (P<0.05) in ducks fed the RMD diets compared with those fed SM diets with a substantial increase (P=0.006) in plasma content of malondialdehyde (MDA). Egg yolks from ducks fed SO diets had higher proportions of polyunsaturated fatty acids (PUFA) and lower saturated and monounsaturated fatty acids compared with CO diets (P<0.001). Similarly, ducks fed RMD diets had a higher content of PUFA and n-6/n-3 ratio in fresh yolks (P<0.001), and increased salted yolk MDA, carbonylated proteins content and incidence of hard salted yolks (P<0.05) compared with SM diets. Scanning electron microscopy showed that salted yolks contained rougher polyhedral granules and fewer fat droplets, and were surrounded with a layer of bunchy fibers in ducks fed SO+RMD than those fed CO+SM diet. In conclusion, the current study showed that feeding laying ducks with diets containing SO or RMD reduced antioxidant capacity and increased egg yolk concentrations of PUFA. It appeared that egg yolks from ducks fed these diets were more sensitive to lipid peroxidation and protein oxidation during salting, and reduced the quality of salted yolks.
The mammalian target of rapamycin (mTOR) has been shown to be involved in lipopolysaccharide (LPS)-induced immune responses in many mammal cells. Here, we suggest that the mTOR pathway is involved in the intestinal inflammatory responses evoked by LPS treatment in chicken embryos. The intestinal tissue from Specific pathogen free chick embryos was cultured in the presence of LPS for 2 h. Secretory immunoglobulin A (sIgA) concentrations, messenger RNA (mRNA) expression of cytokines, and protein levels of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), mTOR and p70 ribosomal S6 kinase (p70S6K) were determined. The results showed that LPS treatment increased sIgA concentrations in a dose-dependent manner. The mRNA levels of interleukine (IL)-6, IL-8, IL-10, tumor necrosis factor-α and Toll-like receptor (TLR) 4 were upregulated by LPS treatment (P<0.05). Lipopolysaccharide increased the phosphorylation of Jun N-terminal kinase (JNK), p38 MAPK and NF-κB (P<0.05) while decreasing the phosphorylation level of mTOR (P<0.05). Supplementation of leucine at doses of 10, 20 and 40 mM dose-dependently decreased sIgA production. Leucine supplementation at 40 mM restored the phosphorylation level of mTOR and p70S6K while suppressing the phosphorylation levels of NF-κB (P<0.05) and partially down-regulating the phosphorylation of p38 MAPK and JNK. The transcription of IL-6 was significantly decreased by leucine supplementation. These results suggested that leucine could alleviate LPS-induced inflammatory responses by down-regulating NF-κB signaling pathway and evoking mTOR/p70S6K signaling pathway, which may involve in the regulation of the intestinal immune system in chicken embryos.
Self-report measurement instruments are commonly used to screen for mental health disorders in Low and Middle-Income Countries (LMIC). The Western origins of most depression instruments may constitute a bias when used globally. Western measures based on the DSM, do not fully capture the expression of depression globally. We developed a self-report scale design to address this limitation, the International Depression Symptom Scale-General version (IDSS-G), based on empirical evidence of the signs and symptoms of depression reported across cultures. This paper describes the rationale and process of its development and the results of an initial test among a non-Western population.
We evaluated internal consistency reliability, test–retest reliability and inter-rater reliability of the IDSS-G in a sample N = 147 male and female attendees of primary health clinics in Yangon, Myanmar. For criterion validity, IDSS-G scores were compared with diagnosis by local psychiatrists using the Structured Clinical Interview for DSM (SCID). Construct validity was evaluated by investigating associations between the IDSS-G and the Patient Health Questionnaire (PHQ), impaired function, and suicidal ideation.
The IDSS-G showed high internal consistency reliability (α = 0.92), test–retest reliability (r = 0.87), and inter-rater reliability (ICC = 0.90). Strong correlations between the IDSS-G and PHQ-9, functioning, and suicidal ideation supported construct validity. Criterion validity was supported for use of the IDSS-G to identify people with a SCID diagnosed depressive disorder (major depression/dysthymia). The IDSS-G also demonstrated incremental validity by predicting functional impairment beyond that predicted by the PHQ-9. Results suggest that the IDSS-G accurately assesses depression in this population. Future testing in other populations will follow.
Lattice Boltzmann method (LBM) is adopted to compute two and three-dimensional lid driven cavity flows to examine the influence of memory management on the computational performance using Graphics Processing Unit (GPU). Both single and multi-relaxation time LBM are adopted. The computations are conducted on nVIDIA GeForce Titan, Tesla C2050 and GeForce GTX 560Ti. The performance using global memory deteriorates greatly when multi relaxation time (MRT) LBM is used, which is due to the scheme requesting more information from the global memory than its single relaxation time (SRT) LBM counterpart. On the other hand, adopting on chip memory the difference using MRT and SRT is not significant. Also, performance of LBM streaming procedure using offset reading surpasses offset writing ranging from 50% to 100% and this applies to both SRT and MRT LBM. Finally, comparisons using different GPU platforms indicate that Titan as expected outperforms other devices, and attains 227 and 193 speedup over its Intel Core i7-990 CPU counterpart and four times faster than GTX 560Ti and Tesla C2050 for three dimensional cavity flow simulations respectively with single and double precisions.
Introduction: High-quality cardiopulmonary resuscitation (CPR) is essential for patient survival. Typically, CPR quality is only measured during the first 10 minutes of resuscitation. There is limited research examining the quality of CPR over the entire duration of resuscitation.Objective: To examine the quality of CPR over the entire duration of resuscitation and correlate the quality of CPR to patient survival. Methods: This was a retrospective observational study using data from the Toronto RescuNET Epistry-Cardiac Arrest database. We included consecutive, adult (>18) OHCA treated by EMS between January 1, 2014 and September 30, 2015. High-quality CPR was defined, in accordance with 2015 AHA Guidelines, as a chest compression rate of 100-120/min, depth of 5.0-6.0 cm and chest compression fraction (ccf) of >0.80. We further categorized high-quality resuscitation as meeting benchmarks >80% of the time, moderate-quality between 50-80% and low-quality meeting benchmarks <50% of the resuscitation. We used multivariable logistic regression to determine association between variables of interest, including CPR quality metrics, and survival to hospital discharge. Results: A total of 5,208 OHCA met our inclusion criteria with a survival rate of 8%. The median (IQR) duration of resuscitation was 23.0 min (15.0,32.7). Overall CPR quality was considered high-quality for ccf in 81% of resuscitation episodes, 41% for rate, and 7% for depth. The percentage of resuscitations meeting the quality benchmarks differed between survivors and non-survivors for both depth (15% vs 6%) and ccf (61% vs 83%) (P value <0.001). After controlling for Utstein variables maintaining a chest compression depth within recommendations for >80% showed a trend towards improved survival (OR 1.68, 95% CI 0.96, 2.92). Other variables associated with survival were public location, initial CPR by EMS providers or bystanders, witnessed cardiac arrest (EMS or bystander), and initial shockable rhythm. Increasing age and longer duration of resuscitation were associated with decreased survival. Conclusion: Overall, EMS providers were not able to maintain rate or depth within guideline recommendations for the majority of the duration of resuscitation. Maintaining chest compression depth for greater than 80% of the resuscitation showed a trend towards increased survival from OHCA.
A 480 year record of the oxygen-isotope ratios, dust content, chemical species and net accumulation from ice cores drilled in 1989 90 on Dyer Plateau in the Antarctic Peninsula is presented. The continuous analyses of small (sub-annual) samples reveal well-preserved annual variations in both sulfate content and δ18O, thus allowing an excellent time-scale to be established.
This history reveals a recent pronounced warming in which the last two decades have been among the warmest in the last five centuries. Furthermore, unlike in East Antarctica, on Dyer Plateau conditions appear to have been fairly normal from AD 1500 to 1850 with cooler conditions from 1850 to 1930 and a warming trend dominating since 1930. Reconstructed annual layer thicknesses suggest an increase in net accumulation beginning early in the 19th century and continuing to the present. This intuitive conflict between increasing net accumulation and depleted δ18O (cooler climate) in the 19th century appears widespread in the peninsula region and challenges our understanding of the physical relationships among moisture sources, air temperatures and snow accumulation. The complex meteorological regime in the Antarctic Peninsula region complicates meaningful interpretation of proxy indicators and results in a strong imprint of local high-frequency processes upon the larger-scale climate picture.
This paper investigates the rupture problem of a thin micropolar liquid film under a magnetic field on a horizontal plate, using long-wave perturbation to resolve nonlinear evolution equations with a free film interface. The governing equation is resolved using a finite difference method as part of an initial value problem for spatial periodic boundary conditions. The effect of a micropolar liquid under a magnetic field on the nonlinear rupture mechanism is studied in terms of the micropolar parameter, R, the Hartmann constant, m and the initial disturbance amplitude, H0. Modeling results indicate that the R, m and H0 parameters strongly affect the film flow. Enhancing the micropolar and magnetic effects is found to delay the rupture time. In addition, the results show that the film rupture time increases as the values of initial disturbance magnitude decrease. The micropolar and magnetic parameters indeed play a significant role in the film flow on a horizontal plate. Moreover, the optimum conditions can be found to alter stability of the film flow by controlling the applied magnetic field.
In linear system, in-plane motions are decoupled from out-of-plane motions for planar frame structures. A theoretical method is proposed that permits the efficient calculations of modal characteristics of planar multi-story frame structures. There are 3 × m beam components for a planar m-story frame structure. By analyzing the transverse and longitudinal motions of each component simultaneously and considering the compatibility requirements across each frame joint, the undetermined variables of the entire m-story frame structure system can be reduced to six, regardless of the number of stories, and that can be determined by the application of the boundary conditions. The main feature of this method is to decrease the dimensions of the matrix involved in the finite element methods and certain other analytical methods.
The study investigates three-dimensional kinematics of lower limb for female Chinese population during normal squatting activity. 25 young female and 25 elder female Chinese subjects were recruited. With each subject's data collected, the means of three-dimensional rotation angles of knee, hip, and ankle joints of those two groups were calculated and analyzed. Measured results showed that the maximal eccentric range of hip flexion/extension of 128.6° for the young female group (P < 0.05) was compared with that of 158.8° for the elder female group. Thus, the elder female undergoes more hip flexion/extension angles than the young female in the posture of squatting. The mean range of motion (ROM) of knee flexion/extension was 140.2° for the young female group and 138.7° (significant level P > 0.05) for the elder female group. The mean ROM of ankle flexion/extension was 47.90° for the young female group and 31.9° (P > 0.05) for the elder female group. The ROMs obtained in the experiment during squatting were greater than the reported ones achieved after joint arthroplasty. These data may be invaluable in providing designers of lower limb prosthesis with basic mechanical parameters, and assessing the effect of kinematics of low limb on rehabilitation for the Chinese population.
Studies have long noted the influence of stone package size and reduction intensity on lithic assemblage composition, particularly in the form of flake size distributions. However, it remains difficult to distinguish objectively the effect of either factor in archaeological contexts without controlling for the variation in one of the two variables. Here we report on an experimental study designed to test the null hypotheses that original stone size and reduction intensity have no impact on the size distribution of lithic flake debris produced during core reduction. Results indicate statistically significant influence from original stone size but not reduction intensity, although the effects from the former are low enough to be considered trivial. In reviewing a sequence of archaeological assemblages from a Middle Paleolithic site, all exhibit an excess of smallsized materials in comparison to the experimental data. When exceptionally high frequencies of the smaller size classes occur, taphonomic processes are clearly responsible.
Gilliland et al. (2000) have reported HST photometric observations of 34000 stars in the globular cluster 47 Tuc, showing an absence of close-in giant planets in that cluster relative to their frequency in the solar neighborhood. Here we describe the methods of time-series analysis that were used to search the 47 Tuc data for transits by giant extrasolar planets, and the means by which these methods were validated.
Gamma Ray Bursts (GRBs) have puzzled astronomers since their discovery more than 20 years ago. As no counterparts at wavelengths other than X- and γ-rays have yet been found the identification of the sources is still missing. Theoretical explanations range from colliding comets (1993) and merging neutron stars (1982) to more exotic objects, such as superconducting cosmic strings (1988). Data accumulated until now still do not discriminate between these models, although results from the BATSE (Burst and Transient Source Experiment) instrument aboard the Compton Gamma Ray Observatory (CGRO) strongly favor extragalactic models.
The Energetic Gamma Ray Experiment Telescope (EGRET) aboard CGRO has s ofar detected photons from 5 GRBs with its spark chamber. These are the highest energy γ-rays associated with GRBs to date. In this work we review previously published data and summarize the properties of these events. Elsewhere we present possible constraints from the data on the models proposed to explain GRBs.
This study explored the target sound source location at unknown situation and processed the received signal to determine the location of the target, including the reconstructed signal of source immediately. In this paper, it used triangulation sound sources localization and time reversal method (TRM) to reconstruct the source signals. The purpose is to use a sound source localization method with a simple device to quickly locate the position of the sound source. This method uses the microphone array to measure signal from the target sound source. Then, the sound source location is calculated and is indicated by Cartesian coordinates. The sound source location is then used to evaluate free field impulse response function which can replace the impulse response function used in time-reversal method. This process reduces the computation time greatly which makes possible for a real time source localization and source signal separation.
This paper intends to develop a target trajectory estimation algorithm with application to the ballistic target estimation in the terminal phase. The proposed design is based on the application of a second-order extended state observer (ESO) technique using target information acquired from the seeker to estimate the trajectory of manoeuverable ballistic targets. Satisfactory results have been received while applying the design in estimation of either two-dimenional or three-dimentional target evasive acceleration via computer simulation.
The current sample of star clusters (SCs) is still incomplete beyond 1.8 kpc. The Pan-STARRS1 with its wide field of views and sensitive cameras provides us an opportunity to identify and characterize SCs as much as possible. By using a star counting algorithm, we obtained a total of 491 stellar density enhancements in a field of 20° × 20° toward the Galactic Anti-Center (GAC), of which 50 are known SCs. The remaining 441 candidates are verified with radii, interstellar reddening, distances, and ages with proper motions and multiple bands photometries. Our results push the completeness of SCs almost near the edge of GAC. With the revised SC sample, the separation between Sagittarius and Perseus arms are about 3.2 ± 0.2 kpc and the widths of the nearby spiral arms—Sagittarius, Orion, and Perseus—with are 1.4 ± 0.1, 1.6 ± 0.1, and 3.3 ± 0.2 kpc, respectively.