Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports

The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis

Influence of tides on melting and freezing beneath Filchner-Ronne Ice Shelf, Antarctica

An isopycnic coordinate ocean circulation model is applied to the ocean cavity beneath Filchner-Ronne Ice Shelf, investigating the role of tides on sub-ice shelf circulation and ice shelf basal mass balance. Including tidal forcing causes a significant intensification in the sub-ice shelf circulation, with an increase in melting (3-fold) and refreezing (6-fold); the net melt rate and seawater flux through the cavity approximately doubles. With tidal forcing, the spatial pattern and magnitude of basal melting and freezing generally match observations. The 0.22 m a(-1) net melt rate is close to satellite-derived estimates and at the lower end of oceanographic values. The Ice Shelf Water outflow mixes with shelf waters, forming a cold (<-1.9 degrees C), dense overflow (0.83 Sv) that spills down the continental slope. These results demonstrate that tidal forcing is fundamental to both ice shelf-ocean interactions and deep-water formation in the southern Weddell Sea. Citation: Makinson, K., P. R. Holland, A. Jenkins, K. W. Nicholls, and D. M. Holland (2011), Influence of tides on melting and freezing beneath Filchner-Ronne Ice Shelf, Antarctica, Geophys. Res. Lett., 38, L06601, doi: 10.1029/2010GL046462

Introducing Exclusion Logic as a Deontic Logic

This paper introduces Exclusion Logic - a simple modal logic without negation or disjunction. We show that this logic has an efficient decision procedure. We describe how Exclusion Logic can be used as a deontic logic. We compare this deontic logic with Standard Deontic Logic and with more syntactically restricted logics

Hydrography and circulation in the Filchner Depression, Weddell Sea, Antarctica

Cold and dense ice shelf water (ISW) emerging from the Filchner-Ronne Ice Shelf cavity in the southwestern Weddell Sea flows northward through the Filchner Depression to eventually descend the con- tinental slope and contribute to the formation of bottom water. New ship-born observations of hydrogra- phy and currents from Filchner Depression in January 2013 suggest that the northward flow of ISW takes place in a middepth jet along the eastern flank of the depression, thus questioning the traditional view with outflow along the western flank. This interpretation of the data is supported by results from a regional numerical model, which shows that ISW flowing northward along the eastern coast of Berkner Island turns eastward and crosses the depression to its eastern side upon reaching the Filchner ice front. The ice front represents a sudden change in the thickness of the water column and thus a potential vorticity barrier. Transport estimates of northward ISW flux based on observations ranges from 0.2 to 1.0 Sv.publishedVersio

Safety, the Preface Paradox and Possible Worlds Semantics

This paper contains an argument to the effect that possible worlds semantics renders semantic knowledge impossible, no matter what ontological interpretation is given to possible worlds. The essential contention made is that possible worlds semantic knowledge is unsafe and this is shown by a parallel with the preface paradox

Ice stream subglacial access for ice-sheet history and fast ice flow: the BEAMISH Project on Rutford Ice Stream, West Antarctica and initial results on basal conditions

Three holes were drilled to the bed of Rutford Ice Stream, through ice up to 2154 m thick, to investigate the basal processes and conditions associated with fast ice flow and the glacial history of the West Antarctic Ice Sheet. A narrative of the drilling, measuring and sampling activities, as well as some preliminary results and initial interpretations of subglacial conditions, is given. These were the deepest subglacial access holes ever drilled using the hot-water drilling method. Samples of bed and englacial sediments were recovered, and a number of instruments were installed in the ice column and the bed. The ice–bed interface was found to be unfrozen, with an existing, well-developed subglacial hydrological system at high pressure, within ~1% of the ice overburden. The bed itself comprises soft, water-saturated sediments, consistent with previous geophysical interpretations. Englacial sediment quantity varies significantly between two locations ~2 km apart, and possibly over even shorter (~20 m) distances. Difficulties and unusual observations encountered while connecting to the subglacial hydrological system in one hole possibly resulted from the presence of a large clast embedded in the bottom of the ice

Regulation of Thalamic and Cortical Network Synchrony by Scn8a.

Voltage-gated sodium channel (VGSC) mutations cause severe epilepsies marked by intermittent, pathological hypersynchronous brain states. Here we present two mechanisms that help to explain how mutations in one VGSC gene, Scn8a, contribute to two distinct seizure phenotypes: (1) hypoexcitation of cortical circuits leading to convulsive seizure resistance, and (2) hyperexcitation of thalamocortical circuits leading to non-convulsive absence epilepsy. We found that loss of Scn8a leads to altered RT cell intrinsic excitability and a failure in recurrent RT synaptic inhibition. We propose that these deficits cooperate to enhance thalamocortical network synchrony and generate pathological oscillations. To our knowledge, this finding is the first clear demonstration of a pathological state tied to disruption of the RT-RT synapse. Our observation that loss of a single gene in the thalamus of an adult wild-type animal is sufficient to cause spike-wave discharges is striking and represents an example of absence epilepsy of thalamic origin