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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.
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.
Absolute K-shell ionization cross sections were measured for Ti, Co, Ge, Rb, and Sn for incident oxygen ions from 16-44 MeV. The x-rays were measured with a high resolution Si(Li) detector (166 eV at 5.9 keV). All of the data represents cross section measurements for thin targets. The measured cross sections for these elements are compared to the theoretical predictions of the Binary Encounter Approximation (BEA). Kα/Kβ ratios and energy shifts were also extracted from the data. The experimental data are compared to measured cross sections for other elements to give an overview of the systematics for oxygen ion induced x-ray production cross sections in this energy range. Some comment will also be given in regard to the use of oxygen ions to measure the parameters associated with ion implanted semiconductors.
The capture of volatile radioactive iodine-129 is an important process for nuclear fission. Biphenyl-bridged wrinkled mesoporous silica shows similar performance for iodine sequestration to commercial Ag-mordenite and avoids the use of expensive silver. The biphenyl-wrinkled mesoporous silica nanoparticles function as a scaffold for biphenyl groups and also as a fluorescent indicator for the loading of iodine. The nanoparticles have a surface area of 973 m2/g and the biphenyl molecules form an electron charge-transfer complex with iodine. Iodine was loaded into the biphenyl-bridged wrinkled mesoporous silica (BWMS) at 19 ± 0.2 % loading by mass.
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.
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.
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.
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 determine the impact of recurrent Clostridium difficile infection (RCDI) on patient behaviors following illness.
Using a computer algorithm, we searched the electronic medical records of 7 Chicago-area hospitals to identify patients with RCDI (2 episodes of CDI within 15 to 56 days of each other). RCDI was validated by medical record review. Patients were asked to complete a telephone survey. The survey included questions regarding general health, social isolation, symptom severity, emotional distress, and prevention behaviors.
In total, 119 patients completed the survey (32%). On average, respondents were 57.4 years old (standard deviation, 16.8); 57% were white, and ~50% reported hospitalization for CDI. At the time of their most recent illness, patients rated their diarrhea as high severity (58.5%) and their exhaustion as extreme (30.7%). Respondents indicated that they were very worried about getting sick again (41.5%) and about infecting others (31%). Almost 50% said that they have washed their hands more frequently (47%) and have increased their use of soap and water (45%) since their illness. Some of these patients (22%–32%) reported eating out less, avoiding certain medications and public areas, and increasing probiotic use. Most behavioral changes were unrelated to disease severity.
Having had RCDI appears to increase prevention-related behaviors in some patients. While some behaviors are appropriate (eg, handwashing), others are not supported by evidence of decreased risk and may negatively impact patient quality of life. Providers should discuss appropriate prevention behaviors with their patients and should clarify that other behaviors (eg, eating out less) will not affect their risk of future illness.
U60 ([UO2(O2)(OH)]6060− in water) is a uranyl peroxide nanocluster with a fullerene topology and Oh symmetry. U60 clusters can exist in crystalline solids or in liquids; however, little is known of their behavior at high pressures. We compressed the U60-bearing material: Li68K12(OH)20[UO2(O2)(OH)]60(H2O)310 (
; a = 37.884 Å) in a diamond anvil cell to determine its response to increasing pressure. Three length scales and corresponding structural features contribute to the compression response: uranyl peroxide bonds (<0.5 nm), isolated single nanoclusters (2.5 nm), and the long-range periodicity of nanoclusters within the solid (>3.7 nm). Li68K12(OH)20[UO2(O2)(OH)]60(H2O)310 transformed to a tetragonal structure below 2 GPa and irreversibly amorphized between 9.6 and 13 GPa. The bulk modulus of the tetragonal U60-bearing material was 25 ± 2 GPa. The pressure-induced amorphous phase contained intact U60 clusters, which were preserved beyond the loss of long-range periodicity. The persistence of U60 clusters at high pressure may have been enhanced by the interaction between U60 nanoclusters and the alcohol pressure medium. Once formed, U60 nanoclusters persist regardless of their associated long-range ordering—in crystals, amorphous solids, or solutions.
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.
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.
Plant defence systems can be induced by biotic and abiotic stress. Experiments were undertaken to explore the feasibility of different fungal proteins for the reduction of vegetable diseases. Total proteins purified from three soil-borne and five foliar fungal pathogens had no fungistatic effects nor did they trigger hypersensitive reactions on test plants. The abilities to promote plant growth and to reduce disease severity varied among test proteins and plants. Depending on test proteins, experiments have demonstrated that exogenous application of fungal proteins could reduce Alternaria brassicicola-induced black spot severity on cabbage, Colletotrichum spp.-induced anthracnose on Chinese cabbage and cucumber, Rhizoctonia solani-induced damping-off on sweet pepper and Chinese cabbage, and powdery mildew on cucumber seedlings. An Alternariaprotein effector 1 (Ape1)-coding gene was cloned from two Alternaria spp. and expressed in Escherichia coli. The expressed Ape1 reduced anthracnose incidence on cucumber leaves, indicating that Ape1 was the primary activator in the crude protein extracts responsible for disease reduction. Application of Alternaria proteins onto Chinese cabbage seedlings caused an increase of phenylalanine ammonia lyase and peroxidase activities in treated seedlings, which may have played a role in host defence.
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.
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.