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Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic, heterogenous, life-threatening disease. Patisiran resulted in significant improvement in neuropathy and QoL at 18-months compared to placebo, and was generally well-tolerated in the Phase 3 APOLLO study. Methods: Multi-center, OLE study to evaluate the efficacy and safety of long-term patisiran dosing for ≤ 5 years in hATTR amyloidosis patients with polyneuropathy who have completed the APOLLO study (NCT02510261). Endpoints include safety, tolerability and long-term efficacy of patisiran. Measures of clinical benefit are the same endpoints used in APOLLO including changes in mNIS+7 composite neuropathy impairment score and QoL (Norfolk QoL-DN) Results: As of December 2017, 184 of 186 (99%) patients who completed APOLLO and 25 patients from the Ph 2 OLE study enrolled in the Global OLE study. Baseline data for 211(APOLLO/placebo, n=49; APOLLO/patisiran, n=137 and patisiran Ph 2 OLE, n=25) patients included: median age 61 years (26-84); 74% males; 46% V30M. Interim safety data and 12-month efficacy results will be presented. Conclusions: The global OLE study includes a diverse population of hATTR amyloidosis patients. Interim data will include the long-term safety and maintenance of effect in patients continuing on patisiran, as well as the impact of treatment with patisiran on patients previously treated with placebo.
Sleeve coldworking (SCW) is a mechanical process used in the aircraft industry to strengthen fastener holes of structural parts. By cold-expanding the holes, compressive residual stresses and a high dislocation density are introduced around the holes, the effect of which is to counteract the initiation and propagation of fatigue cracks and thus increase the fatigue life of the parts. The knowledge of residual stress due to SCW is therefore crucial for assessing the fatigue properties of a treated part. In this study, residual stresses were investigated, by employing neutron and X-ray diffraction methods, in a lug specimen that was sleeve coldworked and fatigued.
The specimen had been used for testing the influence of the SCW process on fatigue life and crack propagation behaviour under constant amplitude or variable amplitude cyclic loading.
Hemostasis, a process which causes bleeding to stop, can be enhanced using chitosan; but the detailed mechanism is unclear. Red blood cells (RBCs) adhere to chitosan because of their opposite charges, but the adhesion force is small, 3.83 pN as measured here using an optical tweezer, such that the direct adhesion cannot be the sole cause for hemostasis. However, it was observed in this study that layer structures of aggregated RBCs were formed next to chitosan objects in both static and flowing environments, but not formed next to cotton and rayon yarns. The layer structure is the clue for the initiation of hemostatsis. Through the supporting measurements of zeta potentials of RBCs and pH's using blood-chitosan mixtures, it is proposed here that the formation of the RBC layer structure next to chitosan objects is due to the reduction of repulsive electric double layer force between RBCs, because of the association of H+ deprotonated from chitosan with COO− on RBC membrane, under the DLVO (Derjaguin-Landau-Verwey-Overbeek) theory. The results are beneficial for designing effective chitosan-based wound dressings, and also for general biomedical applications.
Using an age-structured process-based simulation model for diamondback moth (DBM), we model the population dynamics of this major Brassica pest using the cropping practices and climate of Guangdong, China. The model simulates two interacting sub-populations (demes), each representing a short season crop. The simulated DBM abundance, and hence pest problems, depend on planting regime, crop hygiene and biological control. A continuous supply of hosts, a low proportion of crop harvested and long residue times between harvest and replanting each exacerbate pest levels. Biological control provided by a larval parasitoid can reduce pest problems, but not eliminate them when climate is suitable for DBM and under certain planting practices. The classic Integrated Pest Management (IPM) method of insecticide application, when pest threshold is reached, proved effective and halved the number of insecticide sprays when compared with the typical practice of weekly insecticide application.
Curcumin has been attributed with antioxidant, anti-inflammatory, antibacterial activities, and has shown highly protective effects against enteropathogenic bacteria and mycotoxins. Ochratoxin A (OTA) is one of the major intestinal pathogenic mycotoxins. The possible effect of curcumin on the alleviation of enterotoxicity induced by OTA is unknown. The effects of dietary curcumin supplementation on OTA-induced oxidative stress, intestinal barrier and mitochondrial dysfunctions were examined in young ducks. A total of 540 mixed-sex 1-day-old White Pekin ducklings with initial BW (43.4±0.1 g) were randomly assigned into controls (fed only the basal diet), a group fed an OTA-contaminated diet (2 mg/kg feed), and a group fed the same OTA-contaminated feed plus 400 mg/kg of curcumin. Each treatment consisted of six replicates, each containing 30 ducklings and treatment lasted for 21 days. There was a significant decrease in average daily gain (ADG) and increased feed : gain caused by OTA (P<0.05); curcumin co-treatment prevented the decrease in BW and ADG compared with the OTA group (P<0.05). Histopathological and ultrastructural examination showed clear signs of enterotoxicity caused by OTA, but these changes were largely prevented by curcumin supplementation. Curcumin decreased the concentrations of interleukin-1β, tumor necrosis factor-α and malondialdehyde, and increased the activity of glutathione peroxidase induced by OTA in the jejunal mucosa of ducks (P<0.05). Additionally, curcumin increased jejunal mucosa occludin and tight junction protein 1 mRNA and protein levels, and decreased those of ρ-associated protein kinase 1 (P<0.05). Notably, curcumin inhibited the increased expression of apoptosis-related genes, and downregulated mitochondrial transcription factors A, B1 and B2 caused by OTA without any effects on RNA polymerase mitochondrial (P<0.05). These results indicated that curcumin could protect ducks from OTA-induced impairment of intestinal barrier function and mitochondrial integrity.
Iron-deficiency anemia is a public health concern that frequently occurs in pregnant mammals and neonatal offspring. Ferrous N-carbamylglycinate chelate (Fe-CGly) is a newly designed iron fortifier with proven effects in iron-deficient rats and weanling piglets. However, the effects of this new compound on pregnant mammals are unknown. Therefore, this experiment was conducted to evaluate the effects of Fe-CGly on sow reproductive performance and iron status of both sows and neonatal piglets. A total of 40 large-white sows after second parity were randomly assigned to two groups (n=20). They were receiving a diet including 80 mg Fe/kg as FeSO4 or Fe-CGly, respectively, from day 85 of gestation to parturition. The serum (day 110 of pregnancy) and placentas of sows were sampled. Litter size, mean weight of live born piglets, birth (live) litter weight, number of live born piglets, and the number of still-born piglets, mummies, and weak-born piglets were recorded. Once delivered, eight litters were randomly selected from the 20 litters per treatment, and one new-born male piglet (1.503±0.142 kg) from each selected litter was slaughtered within 3 h after birth from the selected litters, without colostrum ingestion. The serum, longissimus muscle, liver and kidneys of the piglets were collected. The iron status of the serum samples and the messenger RNA level of iron-related genes in the placenta, liver and kidney were analyzed. The results showed that litter weight of live born piglets was higher (P=0.030) in the Fe-CGly group (19.86 kg) than in the FeSO4 group (17.34 kg). Fe-CGly significantly increased placental iron concentration (P<0.05) of sows. It also significantly increased iron saturation and reduced the total iron-binding capacity of piglets (P<0.05) at birth. However, the results revealed that supplementation of Fe-CGly in sows reduced liver and kidney iron concentration of neonatal piglets (P<0.05), indicating decreased iron storage. In addition, the concentration of iron in the colostrum was not significantly changed. Therefore, the present results suggested that replacement of maternal FeSO4 supplement with Fe-CGly in the late-gestating period for sows could improve litter birth weight, probably via enhanced iron transportation in the placenta.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
Hepatitis C virus (HCV) infection is one of the leading causes of death and morbidity associated with liver disease. Risk factors identified for the transmission of HCV include contaminated blood products, intravenous drug use, body piercing, an infected mother at birth, sexual activity, and dental therapy, among others. However, the exact diversity of the HCV genotype and genetic variation among patients with low-risk factors is still unknown. In this study, we briefly described and analysed the genotype distribution and genetic variation of HCV infections with low-risk factors using molecular biology techniques. The results suggested that genotype 1b was predominant, followed by genotypes 2a and 1a. Genetic variations in the 5′ UTR sequences of HCV were identified, including point mutations, deletions, and insertions. The frequency of genetic variations in 1b was higher than in 2a. This study provides considerable value for the prevention and treatment of liver disease caused by HCV among patients with low-risk factors and for the development of HCV diagnostic reagents and vaccines.
To explore the effects of maternal nutrition on offspring muscle characteristics, a total of 56 sows were assigned to one of the four dietary groups during gestation: control (CON), or control diets supplemented with methyl donor (MET), bisphenol A (BPA), and combined BPA and MET (BPA+MET). Compared with CON offspring, MET offspring showed a higher meat redness value, but lower glycogen content in the longissimus thoracis (LT). Moreover, compared with CON offspring, MET offspring showed lower LT glycogen synthase (GS) mRNA levels at birth and the finishing stage, and increased methylation at the GS promoter. Prenatal BPA exposure reduced the pH and redness value of meat, but increased the lightness value, lactate content, glycolytic potential and lactate dehydrogenase (LDH) enzyme activity in the LT muscle. Prenatal BPA exposure increased LDH mRNA levels in the LT muscle at birth and the finishing stage, and reduced methylation at the LDH promoter. Thus, maternal MET affects muscle GS and LDH expression via DNA methylation, thereby resulting in persistent effects on pork quality.
The linear stability boundaries of journal bearings lubricated with a non-Newtonian fluid have been investigated in this paper. Based on the Rabinowitsch fluid model, a non-Newtonian dynamic Reynolds equation for journal bearings is derived and then applied to analyze the linear dynamic characteristics of short journal bearings. Comparing with the Newtonian-lubricant case, the non-Newtonian rheology of dilatant lubricants provides a larger area of linearly stable region. However, the non-Newtonian properties of pseudo-plastic lubricants results in a reverse trend for the short journal bearing.
Mycobacterium marinum, a bacterium found in freshwater and saltwater, can infect persons with direct exposure to fish or aquariums. During December 2013, the New York City Department of Health and Mental Hygiene learned of four suspected or confirmed M. marinum skin or soft tissue infections (SSTIs) among persons who purchased whole fish from Chinese markets. Ninety-eight case-patients with non-tuberculous mycobacteria (NTM) SSTIs were identified with onset June 2013–March 2014. Of these, 77 (79%) were female. The median age was 62 years (range 30–91). Whole genome sequencing of clinical isolates revealed two main clusters and marked genetic diversity. Environmental samples from distributors yielded NTM though not M. marinum. We compared 56 case-patients with 185 control subjects who shopped in Chinese markets, frequency-matched by age group and sex. Risk factors for infection included skin injury to the finger or hand (odds ratio [OR]: 15·5; 95% confidence interval [CI]: 6·9–37·3), hand injury while preparing fish or seafood (OR 8·3; 95% CI 3·8–19·1), and purchasing tilapia (OR 3·6; 95% CI 1·1–13·9) or whiting (OR 2·7; 95% CI 1·1–6·6). A definitive environmental outbreak source was not identified.
The present research aimed to investigate the efficacy of a multifaceted intervention that included motivational interviewing (MI) and psychoeducation in improving medication adherence (MA) among patients with bipolar disorder (BD).
A multicenter, cluster randomized, observer-blind, controlled, parallel-group trial was conducted in ten academic centers in Iran. Patients with BD were randomly assigned to the experimental group (EXP; n = 136) or the usual care group (UC; n = 134). The EXP group received five sessions of MI and psychoeducation together with their family members. The primary outcome measure was changes in scores on the Medication Adherence Rating Scale from baseline to 6 months post-intervention. Other outcome measures included serum levels of mood stabilizers, clinical symptoms, quality of life, as well as measures of intention, beliefs about medicine, perceived behavioral control, automaticity, action and coping planning, and adverse reactions.
Medication adherence improved over time in both groups, but patients in the EXP group improved more (baseline score: 6.03; score at the sixth month: 9.55) than patients in the UC group (baseline score: 6.17; score at the sixth month: 6.67). In addition, patients in the EXP group showed greater improvement than patients in the UC group in almost all secondary outcomes 6 months following the intervention.
Multifaceted interventions that include motivational-interviewing and psychoeducation can significantly improve MA and clinical and functional outcomes in patients with BD.
A compact hybrid rocket motor design that incorporates a dual-vortical-flow (DVF) concept is proposed. The oxidizer (nitrous oxide, N2O) is injected circumferentially into various sections of the rocket motor, which are sectored by several solid fuel “rings” (made of hydroxyl-terminated polybutadiene, HTPB) that are installed along the central axis of the motor. The proposed configuration not only increases the residence time of the oxidizer flow, it also implies an inherent “roll control” capability of the motor. Based on a DVF motor geometry with a designed thrust level of 11.6 kN, the characteristics of the turbulent reacting flow within the motor and its rocket performance were analyzed with a comprehensive numerical model that implements both real-fluid properties and finite-rate chemistry. Data indicate that the vacuum specific impulse (Isp) of the DVF motor could reach 278 s. The result from a preliminary ground test of a lab-scale DVF hybrid rocket motor (with a designed thrust level of 3,000 N) also shows promising performance. The proposed DVF concept is expected to partly resolve the issue of scalability, which remains challenging for hybrid rocket motors development.
We report the temperature dependence of Er optical centers in GaN epilayers prepared by metal-organic chemical vapor deposition under the resonant excitation (4I15/2 → 4I9/2) excitation using a Ti:Sapphire laser (λexc = 809 nm). High resolution infrared spectroscopy and temperature dependence measurements of photoluminescence intensity from Er ions in GaN have been performed to identify the crystal filed splitting of the first excited state, 4I13/2. Here, we have employed a simple approach to determine activation energies which are related to the thermal population of electrons from the lowest level to the higher level of the crystal field splitting of the first excited state.
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, yet the search for definite genetic etiologies remains elusive. Delineating ASD endophenotypes can boost the statistical power to identify the genetic etiologies and pathophysiology of ASD. We aimed to test for endophenotypes of neuroanatomy and associated intrinsic functional connectivity (iFC) via contrasting male youth with ASD, their unaffected brothers and typically developing (TD) males.
The 94 participants (aged 9–19 years) – 20 male youth with ASD, 20 unaffected brothers and 54 TD males – received clinical assessments, and undertook structural and resting-state functional magnetic resonance imaging scans. Voxel-based morphometry was performed to obtain regional gray and white matter volumes. A seed-based approach, with seeds defined by the regions demonstrating atypical neuroanatomy shared by youth with ASD and unaffected brothers, was implemented to derive iFC. General linear models were used to compare brain structures and iFC among the three groups. Assessment of familiality was investigated by permutation tests for variance of the within-family pair difference.
We found that atypical gray matter volume in the mid-cingulate cortex was shared between male youth with ASD and their unaffected brothers as compared with TD males. Moreover, reduced iFC between the mid-cingulate cortex and the right inferior frontal gyrus, and increased iFC between the mid-cingulate cortex and bilateral middle occipital gyrus were the shared features of male ASD youth and unaffected brothers.
Atypical neuroanatomy and iFC surrounding the mid-cingulate cortex may be a potential endophenotypic marker for ASD in males.
To examine the incidence of asthma in adult patients with major depressive disorder (MDD).
From the National Health Insurance database of Taiwan, we identified 30 169 adult patients who were newly diagnosed with MDD between 2000 and 2010. Individuals without depression were randomly selected four times and frequency matched for sex, age and year of diagnosis. Both cohorts were followed-up for the occurrence of asthma up to the end of 2011. Adjusted hazard ratios (aHRs) of asthma were estimated using the Cox proportional hazards method.
The overall incidence of asthma was 1.91-fold higher in the MDD cohort than in the non-depression cohort (7.55 v. 3.96 per 1000 person-years), with an aHR of 1.66 (95% confidence interval (CI) 1.55–1.78). In both cohorts, the incidence of asthma was higher in patients and controls who were female, aged, with comorbidities and users of aspirin or beta-adrenergic receptor blockers. No significant difference was observed in the occurrence of asthma between patients with MDD treated with selective serotonin reuptake inhibitors (SSRIs) and those treated with non-SSRIs (SSRIs to non-SSRIs aHR = 1.03, 95% CI 0.91–1.17).
Adult patients with MDD are at a higher risk of asthma than those without depression are.
Reducers are extensively used in many machines for reducing the speeds of mechanism. This paper proposed a new design of speed reducers to meet the performance requirements in high rigidness and large speed-reduction ratios. The movements of the reducer are designed based on the principles of differential displacements of the deceleration gear rings. The geometric models of the related components were designed using CAD software. The motions of mechanism were simulated for identifying the feasibility of designing including acquiring the kinematic properties. The mathematical models of structural stresses analysis were proposed so that the bending and contact stresses of the gear rings could be evaluated, accordingly. Finite element methods (FEM) were also used to analyze the structural stresses of the reducer. The studied results showed that the bending fracture of the gear rings would prior to its contacting fracture. The allowable loading of the reducer was then established according to the analyzed results of the maximum stresses on various transmitted torques. The methods of reliability evaluation were reported for considering the strength variation and calculating the reliabilities of the reducer at various loadings. The studied results are useful in structural design, stress analysis and reliability evaluation for developing high speed-reduction mechanisms.