Aim
The aim of this paper is to investigate 25‐year trends in community use of prescribed opioid analgesics in Australia, and to map these trends against major changes to opioid registration and ...subsidy.
Methods
We obtained dispensing data from 1990 to 2014 from two sources: dispensing claims processed under Australia's national drug subsidy programme, the Pharmaceutical Benefits Scheme, including under co‐payment records from 2012; and estimates of non‐subsidized medicine use from a survey of Australian pharmacies (until 2011). Utilization was expressed in defined daily doses (DDD)/1000 population/day.
Results
Opioid dispensing increased almost four‐fold between 1990 and 2014, from 4.6 to 17.4 DDD/1000 pop/day. In 1990, weak, short‐acting or orally administered opioids accounted for over 90% of utilization. Use of long‐acting opioids increased over 17‐fold between 1990 and 2000, due primarily to the subsidy of long‐acting morphine and increased use of methadone for pain management. Between 2000 and 2011, oxycodone, fentanyl, buprenorphine, tramadol and hydromorphone use increased markedly. Use of strong opioids, long‐acting and transdermal preparations also increased, largely following the subsidy of various opioids for noncancer pain. In 2011, the most dispensed opioids were codeine (41.1% of total opioid use), oxycodone (19.7%) and tramadol (16.1%); long‐acting formulations comprised approximately half, and strong opioids 40%, of opioid dispensing.
Conclusions
Opioid utilization in Australia is increasing, although these figures remain below levels reported in the US and Canada. The increased use of opioids was largely driven by the subsidy of long‐acting formulations and opioids for the treatment of noncancer pain.
agricultural pesticide poisoning is a major public health problem in the developing world, killing at least 250,000-370,000 people each year. Targeted pesticide restrictions in Sri Lanka over the ...last 20 years have reduced pesticide deaths by 50% without decreasing agricultural output. However, regulatory decisions have thus far not been based on the human toxicity of formulated agricultural pesticides but on the surrogate of rat toxicity using pure unformulated pesticides. We aimed to determine the relative human toxicity of formulated agricultural pesticides to improve the effectiveness of regulatory policy.
we examined the case fatality of different agricultural pesticides in a prospective cohort of patients presenting with pesticide self-poisoning to two clinical trial centers from April 2002 to November 2008. Identification of the pesticide ingested was based on history or positive identification of the container. A single pesticide was ingested by 9,302 patients. A specific pesticide was identified in 7,461 patients; 1,841 ingested an unknown pesticide. In a subset of 808 patients, the history of ingestion was confirmed by laboratory analysis in 95% of patients. There was a large variation in case fatality between pesticides-from 0% to 42%. This marked variation in lethality was observed for compounds within the same chemical and/or WHO toxicity classification of pesticides and for those used for similar agricultural indications.
the human data provided toxicity rankings for some pesticides that contrasted strongly with the WHO toxicity classification based on rat toxicity. Basing regulation on human toxicity will make pesticide poisoning less hazardous, preventing hundreds of thousands of deaths globally without compromising agricultural needs. Ongoing monitoring of patterns of use and clinical toxicity for new pesticides is needed to identify highly toxic pesticides in a timely manner.
Linking integrin conformation to function Askari, Janet A; Buckley, Patrick A; Mould, A. Paul ...
Journal of cell science,
01/2009, Letnik:
122, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Integrins are αβ heterodimeric adhesion receptors that relay signals bidirectionally across the plasma membrane between the extracellular matrix and cell-surface ligands, and cytoskeletal and ...signalling effectors. The physical and chemical signals that are controlled by integrins are essential for intercellular communication and underpin all aspects of metazoan existence. To mediate such diverse functions, integrins exhibit structural diversity, flexibility and dynamism. Conformational changes, as opposed to surface expression or clustering, are central to the regulation of receptor function. In recent years, there has been intense interest in determining the three-dimensional structure of integrins, and analysing the shape changes that underpin the interconversion between functional states. Considering the central importance of the integrin signalling nexus, it is perhaps no surprise that obtaining this information has been difficult, and the answers gained so far have been complicated. In this Commentary, we pose some of the key remaining questions that surround integrin structure-function relationships and review the evidence that supports the current models.
Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can ...worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts <50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit (“much” or “very much” improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia.
AbstractPolarimetry of IGR J1401-4306, a long-period (12.7 h) eclipsing intermediate polar and remnant of Nova Scorpii 1437 AD, reveals periodic variations of optical circular polarization, ...confirming the system as the longest-period eclipsing intermediate polar known. This makes it an interesting system from an evolutionary perspective. The circular polarization is interpreted as optical cyclotron emission from an accreting magnetic white dwarf primary. Based on the polarimetry, we propose that it is a disc-fed intermediate polar. The detection of predominantly negative circular polarization is consistent with only one of the magnetic poles dominating the polarized emission, while the other is mostly obscured by the accretion disc.
Aims
To investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans.
Methods
Indirect ...calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold‐induced BAT activation on 18F‐FDG PET/CT (n = 8) underwent a randomly allocated second 18F‐FDG PET/CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4).
Results
We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold‐induced increase in the metabolic activity of supraclavicular BAT on 18F‐FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not.
Conclusions
Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE.
We conducted time-resolved optical spectroscopy and/or time-series photometry of 15 cataclysmic binaries that were discovered in hard X-ray surveys by the Swift Burst Alert Telescope and the ...International Gamma-Ray Astrophysics Laboratory, with the goal of measuring their orbital periods and searching for spin periods. Four of the objects in this study are new optical identifications: Swift J0535.2+2830, Swift J2006.4+3645, IGR J21095+4322, and Swift J2116.5+5336. Coherent pulsations are detected from three objects for the first time, Swift J0535.2+2830 (1523 s), 2PBC J1911.4+1412 (747 s), and 1SWXRT J230642.7+550817 (464 s), indicating that they are intermediate polars (IPs). We find two new eclipsing systems in time-series photometry: 2PBC J0658.0−1746, a polar with a period of 2.38 hr, and Swift J2116.5+5336, a disk system that has an eclipse period of 6.56 hr. Exact or approximate spectroscopic orbital periods are found for six additional targets. Of note is the long 4.637-day orbit for Swift J0623.9−0939, which is revealed by the radial velocities of the photospheric absorption lines of the secondary star. We also discover a 12.76 hr orbital period for RX J2015.6+3711, which confirms that the previously detected 2.00 hr X-ray period from this star is the spin period of an IP, as inferred by Coti Zelati et al. These results support the conclusion that hard X-ray selection favors magnetic CVs, with IPs outnumbering polars.
A Reverse Shock in GRB 181201A Laskar, Tanmoy; Eerten, Hendrik van; Schady, Patricia ...
The Astrophysical journal,
10/2019, Letnik:
884, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We present comprehensive multiwavelength radio to X-ray observations of GRB 181201A spanning from 150 s to 163 days after the burst, comprising the first joint ALMA-VLA-GMRT observations of a ...gamma-ray burst (GRB) afterglow. The radio and millimeter-band data reveal a distinct signature at 3.9 days, which we interpret as reverse-shock (RS) emission. Our observations present the first time that a single radio-frequency spectral energy distribution can be decomposed directly into RS and forward shock (FS) components. We perform detailed modeling of the full multiwavelength data set, using Markov Chain Monte Carlo sampling to construct the joint posterior density function of the underlying physical parameters describing the RS and FS synchrotron emission. We uncover and account for all discovered degeneracies in the model parameters. The joint RS-FS modeling reveals a weakly magnetized ( 3 × 10−3), mildly relativistic RS, from which we derive an initial bulk Lorentz factor of Γ0 103 for the GRB jet. Our results support the hypothesis that low-density environments are conducive to the observability of RS emission. We compare our observations to other events with strong RS detections and find a likely observational bias selecting for longer lasting, nonrelativistic RSs. We present and begin to address new challenges in modeling posed by the present generation of comprehensive, multifrequency data sets.
Abstract
We report on SALT low-resolution optical spectroscopy and optical/IR photometry undertaken with other SAAO telescopes (MASTER-SAAO and IRSF) of the kilonova AT 2017gfo (a.k.a. SSS17a) in the ...galaxy NGC4993 during the first 10 d of discovery. This event has been identified as the first ever electromagnetic counterpart of a gravitational wave event, namely GW170817, which was detected by the LIGO and Virgo gravitational wave observatories. The event is likely due to a merger of two neutron stars, resulting in a kilonova explosion. SALT was the third observatory to obtain spectroscopy of AT 2017gfo and the first spectrum, 1.2 d after the merger, is quite blue and shows some broad features, but no identifiable spectral lines and becomes redder by the second night. We compare the spectral and photometric evolution with recent kilonova simulations and conclude that they are in qualitative agreement for post-merger wind models with proton:nucleon ratios of Ye = 0.25–0.30. The blue colour of the first spectrum is consistent with the lower opacity of the lanthanide-free r-process elements in the ejecta. Differences between the models and observations are likely due to the choice of system parameters combined with the absence of atomic data for more elements in the ejecta models.
Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity — serotonin toxicity.
Serotonin ...toxicity is characterised by neuromuscular excitation (clonus, hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, diaphoresis, tremor, flushing) and changed mental state (anxiety, agitation, confusion).
Serotonin toxicity can be: mild (serotonergic features that may or may not concern the patient); moderate (toxicity which causes significant distress and deserves treatment, but is not life‐threatening); or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure).
Diagnosis of serotonin toxicity is often made on the basis of the presence of at least three of Sternbach's 10 clinical features. However, these features have very low specificity. The Hunter Serotonin Toxicity Criteria use a smaller, more specific set of clinical features for diagnosis, including clonus, which has been found to be more specific to serotonin toxicity.
There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single‐drug therapy in susceptible individuals.
Treatment should focus on cessation of the serotonergic medication and supportive care. Some antiserotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined.
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