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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.
The thermal transformations which take place in solid methyl-substituted ammonium perchlorates have been studied using high-temperature X-ray diffraction and differential thermal analysis techniques. In the temperature range from 20°C to their decomposition temperature (above 300°C), ammonium perchlorate and tetramethyl ammonium perchlorate undergo only one enantiomorphic phase transition, namely at 240 and 340°C (with decomposition), respectively. This I—II transition is ascribed to the beginning of the free rotation of the ClO4− ions. The rotation of the cations, however, begins below room temperature. If the symmetry of the cation is lowered by having both methyl groups and hydrogens arranged around the nitrogen (as in monomethyl, dimethyl, and trimethyl ammonium perchlorates), there is an additional enantiomorphic phase transition. This I—II transformation is ascribed to the rotation of the cations which have, in the partially substituted ions, two sets of non-equivalent symmetry axes (different moments of inertia). The temperatures of transformation are discussed in terms of the space requirements for rotation. Symmetries and cell dimensions of some modifications were determined.
This article considers two recent books in the history of childhood, youth, and the law: Holly Brewer, By Birth or Consent and Stephen Robertson, Crimes Against Children. It argues that these works mark the emergence of age as a category of analysis in sociolegal studies. It calls for further investigations in the legal history of childhood and youth, outlines several areas of interest, and suggests that attention to age will alter how scholars look at the law by complicating key concepts such as innocence, authority, and citizenship. Studies of age and the law could benefit from cross-cultural and transnational approaches.
Laser-based compact MeV X-ray sources are useful for a variety of applications such as radiography and active interrogation of nuclear materials. MeV X rays are typically generated by impinging the intense laser onto ~mm-thick high-Z foil. Here, we have characterized such a MeV X-ray source from 120 TW (80 J, 650 fs) laser interaction with a 1 mm-thick tantalum foil. Our measurements show X-ray temperature of 2.5 MeV, flux of 3 × 1012 photons/sr/shot, beam divergence of ~0.1 sr, conversion efficiency of ~1%, that is, ~1 J of MeV X rays out of 80 J incident laser, and source size of 80 m. Our measurement also shows that MeV X-ray yield and temperature is largely insensitive to nanosecond laser contrasts up to 10−5. Also, preliminary measurements of similar MeV X-ray source using a double-foil scheme, where the laser-driven hot electrons from a thin foil undergoing relativistic transparency impinging onto a second high-Z converter foil separated by 50–400 m, show MeV X-ray yield more than an order of magnitude lower compared with the single-foil results.
Excavations at several locations in Verteba Cave have uncovered a large amount of human skeletal remains in association with faunal bones and Tripolye material culture. We aim to establish radiocarbon (14C) dates for eight sites and to evaluate whether these deposits are singular events, or slow accumulations over time. 14C measurements, along with stable carbon and nitrogen isotope data from human and faunal remains, were collected from 18 specimens. Stable isotope values were used to evaluate human and animal diet, and whether freshwater reservoir effects offset measured dates. We found diets of the sampled species had limited to no influence from freshwater resources. Human diet appears to be dominated by terrestrial plants and herbivores. Four new sites were identified as Eneolithic. Comparisons of dates from top and bottom strata for two sites (7 and 20) reveal coeval dates, and we suggest that these deposits represent discrete events rather than slow continuous use. Lastly, we identified dates from the Mesolithic (8490±45 BP, 8765±30 BP), Iron Age (2505±20 BP), Slavic state era (1315±25 BP), and Medieval Period (585±15 BP), demonstrating periodic use of the cave by humans prior to and after the Eneolithic.
The analysis of stable isotopes of carbon and nitrogen has been used as a fingerprint for understanding the trophic interactions of organisms. Most of these studies have been applied to free-living organisms, while parasites have largely been neglected. Studies dealing with parasites so far have assessed the carbon and nitrogen signatures in endoparasites or ectoparasites of different hosts, without showing general trends concerning the nutritional relationships within host–parasite associations. Moreover, in most cases such systems involved a single host and parasite species. The present study is therefore the first to detail the trophic interactions of a freshwater monogenean–host model using δ13C and δ15N, where a single monogenean species infects two distinctly different hosts. Host fishes, Labeobarbus aeneus and Labeobarbus kimberleyensis from the Vaal Dam, South Africa, were assessed for the monogenean parasite Paradiplozoon ichthyoxanthon, individuals of which were removed from the gills of the hosts. The parasites and host muscle samples were analysed for signatures of δ13C and δ15N using an elemental analyser connected to an isotope ratio mass spectrometer. Host fish appear to use partly different food sources, with L. aeneus having slightly elevated δ13C signatures compared to L. kimberleyensis, and showed only small differences with regard to their nitrogen signatures, suggesting that both species range on the same trophic level. Carbon and nitrogen signatures in P. ichthyoxanthon showed that the parasites mirrored the small differences in dietary carbon sources of the host but, according to δ15N signatures, the parasite ranged on a higher trophic level than the hosts. This relationship resembles predator–prey relationships and therefore suggests that P. ichthyoxanthon might act as a micropredator, similar to blood-sucking arthropods such as mites and fleas.
To reduce inappropriate antimicrobial prescribing across ambulatory care, understanding the patient-, provider-, and practice-level characteristics associated with antibiotic prescribing is essential. In this study, we aimed to elucidate factors associated with inappropriate antimicrobial prescribing across urgent care, family medicine, and pediatric and internal medicine ambulatory practices.
DESIGN, SETTING, AND PARTICIPANTS
Data for this retrospective cohort study were collected from outpatient visits for common upper respiratory conditions that should not require antibiotics. The cohort included 448,990 visits between January 2014 and May 2016. Carolinas HealthCare System urgent care, family medicine, internal medicine and pediatric practices were included across 898 providers and 246 practices.
Prescribing rates were reported per 1,000 visits. Indications were defined using the International Classification of Disease, Ninth and Tenth Revisions, Clinical Modification (ICD-9/10-CM) criteria. In multivariable models, the risk of receiving an antibiotic prescription was reported with adjustment for practice, provider, and patient characteristics.
The overall prescribing rate in the study cohort was 407 per 1,000 visits (95% confidence interval [CI], 405–408). After adjustment, adult patients seen by an advanced practice practitioner were 15% more likely to receive an antimicrobial than those seen by a physician provider (incident risk ratio [IRR], 1.15; 95% CI, 1.03–1.29). In the pediatric sample, older providers were 4 times more likely to prescribe an antimicrobial than providers aged ≤30 years (IRR, 4.21; 95% CI, 2.96–5.97).
Our results suggest that patient, practice, and provider characteristics are associated with inappropriate antimicrobial prescribing. Future research should target antibiotic stewardship programs to specific patient and provider populations to reduce inappropriate prescribing compared to a “one size fits all” approach.
The decisive victory of Alberto Fujimori and his congressional list in 1995 did not reflect a delegative view of democracy among the Peruvian electorate. Instead of uncritically supporting their reelected president, as a delegative model would predict, Peruvians have rejected the illiberal and possibly unconstitutional policies of his second administration. Relying on public opinion poll data, this study argues that the same issues that facilitated Fujimori’s 1995 landslide will probably work against him in 2000.
Although decentralization is probably the institutional reform most frequently proposed for Third World countries, it has proven to be an elusive topic for both practitioners and analysts of development. Studies of centralization and decentralization are overwhelmingly descriptive, formalistic, or episodic. This article attempts to improve our understanding of how macro-political factors affect the adoption and implementation of decentralization policies in Latin America.
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations.
In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire.
Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery.
Our findings show that 5-HT2AR activation by LSD leads to a hippocampal–prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.
OBJECTIVES/SPECIFIC AIMS: Obstructive lung disease following particulate matter (PM) exposure is a major health concern. Coexisting metabolic syndrome (MetSyn) often occurs. Receptor for advanced glycation end products (RAGE) is highly expressed in the lung, is a strong predictor of FEV1, and is a key mediator of MetSyn. To determine if the loss of RAGE protects from the persistence of effects of particulate associated lung injury in a murine model. METHODS/STUDY POPULATION: Wild type (WT) and RAGE knockout (RKO) mice were exposed to 100 μg of PM (WTC-Aggregate, PM53) or PBS control by oropharyngeal aspiration. Lung function, methacholine challenge, and bronchoalveolar lavage (BAL) were quantified 28 days after PM exposure using flexiVent (Scireq Montreal, QC). BAL was obtained and cell differentials, cytokines and transcription factors were assayed. Bio-volume to airspace ratio and mean chord length were measured (Image J and Adobe Photoshop). RESULTS/ANTICIPATED RESULTS: WT mice were hyper-reactive to methacholine compared with their PBS controls 28 days after a single exposure to PM. They recovered from increased neutrophilia, loss of FEV, decreased compliance, and increased resistance, which were previously observed 24-hours after exposure. RKO were not hyper-reactive when compared with their own PBS controls. Lung histology shows persistence of loss of alveolar space in WT mice exposed to PM after 28 days. Area fraction was significantly higher in PM exposed WT mice after 28 days which was not significant after 24 hours. Mean chord length was significantly shorter for PM exposed at both time points for WT mice. The relative expression of phosphorylated to total CREB and ERK1/2 proteins was lower in RKO PM exposed mice compared with WT PM while STAT3 expression was lower in WT PM compared with WT PBS. PM induced a lower fold change of total proteins from the PBS controls in RKO for CREB, p38, ERK1/2, STAT3, and STAT5. JNK and p70S6k total proteins expressed a decreased fold change in WT PM exposed mice compared with WT PBS controls. DISCUSSION/SIGNIFICANCE OF IMPACT: A single dose of PM can produce persistent airway hyper-reactivity after 28 days of exposure. This PM induced injury is alleviated in the absence of RAGE, similar to what was seen at 24 hours. Inhibiting RAGE may be key to limiting the persistent inflammatory effects of high intensity PM exposure.
Sublimation (vaporization) of the icy component of a cometary nucleus determines the initial composition of the coma gas as it streams outward and escapes. Photolytic reactions in the inner coma, escape of fast, light species such as atomic and molecular hydrogen, and solar wind interaction in the outer coma alter the chemical composition and the physical nature of the coma gas. Models that describe these interactions must include (1) chemical kinetics, (2) coma energy balance, (3) multifluid flow for the rapidly escaping light components, the heavier bulk fluid, and the plasma with separate temperatures for electrons and the remainder of the gas, (4) transition from a collision dominated inner region to free molecular flow of neutrals in the outer region, (5) pickup of cometary ions by the solar wind, (6) counter and cross streaming of neutrals with respect to the plasma which outside of the contact surface also contains solar wind ions, and (7) magnetic fields carried by the solar wind. Progress on such models is described and results including velocity, temperature, and number density profiles for important chemical species are presented and compared with observations.