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Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain
Sibilia Quilici1,
Jeremy Chancellor2Email author,
Mickael Löthgren3,
Dominique Simon4,
Gérard Said5,
Trong Kim Le6,
Ana Garcia-Cebrian7 and
Brigitta Monz8
BMC Neurology20099:6
https://doi.org/10.1186/1471-2377-9-6
© Quilici et al; licensee BioMed Central Ltd. 2009
Few direct head-to-head comparisons have been conducted between drugs for the treatment of diabetic peripheral neuropathic pain (DPNP). Approved or recommended drugs in this indication include duloxetine (DLX), pregabalin (PGB), gabapentin (GBP) and amitriptyline (AMT). We conducted an indirect meta-analysis to compare the efficacy and tolerability of DLX with PGB and GBP in DPNP, using placebo as a common comparator.
We searched PubMed, EMBASE, CENTRAL databases and regulatory websites for randomized, double-blind, placebo-controlled, parallel group or crossover clinical trials (RCTs) assessing DLX, PGB, GBP and AMT in DPNP. Study arms using approved dosages with assessments after 5–13 weeks were eligible. Efficacy criteria were: reduction in 24-hour pain severity (24 h PS) for all three drugs, and response rate (≥ 50% pain reduction) and Patient Global Impression of Improvement/Change (PGI-I/C) for DLX and PGB only. Tolerability criteria included: discontinuation, diarrhoea, dizziness, headache, nausea and somnolence. Direct comparisons versus placebo were conducted with pooled fixed – and random-effects analyses on endpoints reported in at least two studies of each drug. Indirect comparisons were performed between DLX and each of PGB and GBP using Bayesian simulation.
Three studies of DLX, six of PGB, two of GBP and none of AMT met the inclusion criteria. In random-effects and fixed-effects analyses of DLX, PGB and GBP, all were superior to placebo for all efficacy parameters, with some tolerability trade-offs. Indirect comparison of DLX with PGB found no differences in 24 h PS, but significant differences in PGI-I/C, favouring PGB, and in dizziness, favouring DLX were apparent. Comparing DLX and GBP, there were no statistically significant differences.
From the few available studies suitable for indirect comparison, DLX shows comparable efficacy and tolerability to GBP and PGB in DPNP. Duloxetine provides an important treatment option for this disabling condition.
Duloxetine
Neuropathic pain is often associated with diabetic peripheral neuropathy and is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system [1]. In a recent cross-sectional study in the UK, the overall prevalence of chronic (>1 year) painful peripheral neuropathy was estimated to be 16.2% among patients with diabetes compared with 4.9% among matched controls [2]. The rising prevalence of type 2 diabetes is likely to increase the burden of diabetic peripheral neuropathic pain (DPNP) [3].
The main symptoms of DPNP are burning or shooting pain in the lower limbs and feet, usually occurring for more than three months. Currently, there are no approved treatments that restore nerve function. A major goal of pharmacological treatment in DPNP is therefore to control pain. Simple analgesics may provide partial, short-term relief, but more specifically targeted drugs are normally required for sustained control of pain of neuropathic origin.
Amitriptyline, a tricyclic antidepressant (TCA) first marketed in the 1960s, is not licensed for treatment of DPNP. However, along with another TCA (nortriptyline), it is recommended in the British National Formulary as a drug of choice for treating DPNP. More recently, the use of anticonvulsants has been proposed for the treatment of neuropathic pain. Gabapentin is licensed for the treatment of neuropathic pain in Europe and for the treatment of post-herpetic neuralgia, a specific type of neuropathic pain, in the US. Pregabalin was approved in 2004 for the treatment of peripheral neuropathic pain in Europe, and in 2005 for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia (PHN) in the US. Duloxetine is a relatively balanced and potent reuptake inhibitor of serotonin and norepinephrine, approved in Europe and the US for the treatment of DPNP. It was first approved as an antidepressant for the treatment of major depressive disorder (MDD).
The aims of the meta-analysis were twofold. The first was to summarize the efficacy and tolerability of drug treatments licensed or recommended for DPNP by statistically pooling the available data from randomized, placebo-controlled trials. The second aim was to compare the efficacy and tolerability of duloxetine with pregabalin, gabapentin and amitriptyline. As most of the controlled clinical trials of these drugs are comparisons with placebo and very few head-to-head comparisons exist, an indirect approach was chosen using placebo as a common comparator.
A comprehensive and systematic search of the published literature for trials of duloxetine (DLX), pregabalin (PGB), gabapentin (GBP) and amitriptyline (AMT) in the treatment of DPNP was performed during January 2005 using PubMed, EMBASE and CENTRAL databases. The search strategy was not limited by year or language of publication. Internal study reports of all trials of duloxetine in the treatment of DPNP were provided by the primary study sponsor, Eli Lilly and Company. We are not aware of any trials of duloxetine conducted since the date of search. In addition, the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) websites were searched for available reviews of PGB and GBP. As PGB had only recently been licensed for DPNP, it was considered that all trials completed by the manufacturer would be identified through these websites.
Study selection and validity assessment
The drugs considered for inclusion in the meta-analysis were those licensed (DLX, PGB, GBP) or recommended (AMT) for DPNP, subject to a minimum requirement for two eligible studies of any drug. Identified references were screened using title, abstract and keywords. Studies were considered potentially eligible for inclusion in the meta-analyses of each individual drug if they were randomised, double-blind, placebo-controlled trials in diabetic neuropathy or diabetic peripheral neuropathic pain with a treatment duration of 5–13 weeks, or longer provided that results were reported for this duration. Studies could be of parallel group or crossover design, but crossover studies had to demonstrate sufficient washout period, randomisation of the order of study treatment and that subjects had stable disease over the study period. Evidence of sample size calculations for the primary efficacy variable was required, consistent with CONSORT recommendations for the reporting of clinical trials, as adopted by BioMed Central[4] and other journals. Eligibility was confirmed on review of full publications and/or study reports against the above criteria.
Data abstraction
Study design data including design synopsis, treatment comparators, dosage, titration schedule and duration of treatment were abstracted, along with baseline characteristics including summary statistics of pain severity, age and sex. Summary efficacy and tolerability outcomes were also abstracted. Data were entered into spreadsheets by one author (ML) and were verified by another (SQ).
Selection of outcome measures
By assessing the commonality of outcome measures available across drugs and across the eligible studies of each drug, a set of outcomes was identified for which sufficient data were available for pooling, notwithstanding minor differences in reporting.
The primary assessment of treatment efficacy, available for all drugs, was 24-hour average pain severity (24 h PS), treatment response and overall health improvement. 24 h PS was recorded by patients in daily or weekly diaries on an 11-point ordinal scale, ranging from 0 = no pain to 10 = worst pain possible. Treatment efficacy outcomes only partially available were treatment response and patient global impression. Treatment response was defined as at least a 50% reduction in 24 h PS score from baseline, and was reported as proportions of responders. The overall health improvement was measured on the Patient Global Impression of Improvement/Change (PGI-I/C) questionnaire, a 7-point ordinal, categorical scale describing patients' reported impressions ranging from "very much improved" to "very much worse" [5].
The most frequently reported tolerability outcomes were considered. These included premature discontinuation due to lack of efficacy and due to adverse events (AEs), as well as the AE symptoms reported most frequently (>5%) in patients receiving DLX and corresponding with those reported in the studies of PGB and GBP: diarrhoea, dizziness, headache, somnolence and nausea. By definition, only symptoms reported in common between drugs could be included in the indirect meta-analyses. Treatment effects for continuous variables, such as 24 h PS, were estimated as the absolute difference between the mean change from baseline to study endpoint. Treatment effects for discrete variables (PGI-I/C, response rates and AE incidence rates) were estimated as log-odds ratios.
To test for the significance of between-study differences, analysis of variance (ANOVA) tests were used for continuous baseline measures (age, treatment effect) and the Cochrane-Mantel-Haentzel test was used for sex.
Quantitative data synthesis
Direct meta-analyses were performed to estimate effect sizes for each drug compared to placebo, using classical frequentist fixed-effects (FE) and random-effects (RE) models. Studies were pooled by weighting the treatment differences by their inverse variances. Comparisons between drug and placebo were expressed as mean differences (θ) with 95% confidence intervals. Treatment differences between studies were tested using the Mann-Whitney U-test. FE and RE models were estimated and Cochrane Q-tests, I-squared and τ 2 statistics were used to test for and quantify between-study heterogeneity. Forest plots were generated to assess the extent of this visually. Superiority tests were performed for the direct comparisons of each active drug with placebo for each outcome, using a one-sided 95% confidence interval (CI). The number needed to treat (NNT) – the number of patients that need to be treated with drug compared to placebo to obtain one additional responder – and the number needed to harm (NNH) for discontinuation due to AEs were calculated. When 95% CIs for NNTs and NNHs were not significant (e.g. if they included a negative CI bound) the sign ∞ was used for the undefined bound [6]. The NNTs/NNHs were derived from the estimated treatment differences (θ) and from event probabilities in the control group [7].
Due to the absence of head-to-head trials, the comparisons of DLX with the other active treatments were made by means of indirect meta-analyses, using placebo as a common comparator. These were performed using a Bayesian simulation approach. The adjusted outcomes of active treatments vs. placebo from the direct comparison were pooled across available studies, to derive estimates of δ, the mean difference in treatment effect between DLX and each comparator, along with 95% credibility intervals. Non-informative prior distributions of θ and the between-study heterogeneity (τ 2) were used.
Non-inferiority tests were performed for the comparisons of 24 h PS between DLX and the other drugs. A difference of 2 points on the 11-point scale was selected as the non-inferiority margin, based on previous research into the correspondence of 24 h PS scores with "very much improved " and "much improved" ratings on the PGI scale [8]. For the remaining outcomes, for which no consensus exists on the minimum clinically meaningful difference, superiority tests were performed.
Figure 1 presents the results of the literature search, screening and review for those studies deemed eligible for inclusion in the meta-analysis. From 91 potentially relevant publications, 11 were included in the meta-analysis. Of the four randomized studies of AMT potentially eligible, one had a very small sample (n = 25) with no sample size calculation and was, therefore, excluded[9] Two studies included benzotropine as an active placebo (to preserve blinding by mimicking the anticholinergic side-effects of amitriptyline). This precluded any tolerability comparison with no treatment. Of these two studies, one was a crossover study with no washout period. In the other, AMT was not directly compared to placebo. The sole remaining eligible study involving AMT was one of the studies of PGB (DPN-040), which included AMT as a control in addition to placebo. Due to the pre-specified minimum requirement for two eligible studies of any drug, AMT was eliminated from the meta-analysis. Hence, the meta-analysis included DLX (three unpublished studies at the time of searching, available as manufacturer's study reports)[10, 11], GBP (two published studies)[12, 13] and PGB (six studies, comprising four unpublished at the time of searching, available as EMEA Scientific Discussions, and two published studies) [14–16]. The three DLX studies included 679 patients on active treatment and 339 on placebo; the GBP studies included 114 patients on active treatment and 111 on placebo and the PGB studies included 988 patients on active treatment and 478 on placebo.
Flow diagram of systematic review to identify eligible studies.
For the DLX vs. PGB comparison, three efficacy outcomes were considered: 24 h PS, pain response and PGI-I/PGI-C, and seven tolerability outcomes: premature discontinuation due to adverse events, due to lack of efficacy and due to other reasons, dizziness, somnolence, headache and diarrhoea. For the DLX vs. GBP comparison, only the 24 h PS efficacy comparison was possible due to lack of GBP data. However, all eight tolerability outcomes were possible, comprising the seven described above plus nausea.
Some outcome measures were excluded as they were reported for some but not all of the drugs, or for some but not all trials of a drug. The three studies of DLX included some efficacy outcomes not present in the other drug studies. These included the night pain severity, the Brief Pain Index (BPI), the Clinical Global Impression of Severity (CGI-S), all of which were absent from studies of the other drugs, and the Short Form McGill Pain Questionnaire (SF-MPQ), which was included in two of the six PGB studies and one of the two GBP trials. Because it is an antidepressant, the studies of DLX in DPNP excluded patients with diagnosed depression to avoid biasing estimates of the direct effect of DLX on DPNP. This restriction did not apply to GBP and PGB.
Study characteristics
Table 1 illustrates the design and baseline characteristics of the studies included in the meta-analyses. The treatment duration varied between 5 and 12 weeks and the study dosage of individual drugs varied. Only study arms using therapeutic dosage corresponding to regulatory labelling were eligible for inclusion. In testing for overall between-study heterogeneity, significant differences were detected in the proportions of patients by sex (p < 0.0001) and by co-morbid type 2 diabetes (p < 0.0001), while no significant differences were found in baseline pain severity or age.
Study design and patient baseline characteristics.*
Randomised
patients (N)
(weeks)
Baseline severity
(24-hour
pain intensity
score) Mean (sd)
(% Type 2)
Mean (sd)
DPNP
(sd)
Gender (% male)
HMAW
60 mg QD
60 mg BID
HMAVa
HMAVb
DPN-029
100 mg TID
50 mg TID
150 mg BID
150/300 mg BID
600 mg QID
Flexible dose
150 – 600 mg
Backonja
1200 mg TID
*Note: duloxetine trial arms with dose 20 mg QD and pregabalin trial arms with dose 25 mg TID were excluded from the meta-analysis;
aQD: Once daily; BID: Twice daily; TID: Three times daily.
Direct comparison results
As heterogeneity between studies measured by the Q-test was not significant and the FE and RE models produced similar estimates of treatment effect for the primary and the other outcomes, only the results from the random-effects models are reported here.
All three drugs were superior to placebo for all efficacy parameters. (Please note: effects (θ) favouring drug over placebo take a negative sign for the outcome measures 24 h PS, PGI-I/C and tolerability but a positive sign for response). For 24 h PS, θ (95% CIs) were DLX: -1.13 (-1.36; -0.89), PGB: -0.90 (-1.23; -0.57), GBP: -1.44 (-2.21; -0.66). Corresponding θ values for response rate were DLX: 0.86 (0.63; 1.09) with NNT of 5 (3; 7), PGB: 0.84 (0.52; 1.16) with NNT of 5 (4; 8); and for PGI-I/C were DLX: -0.76 (-1.00; -0.51), PGB: -1.29 (-1.72; -0.86).
The forest plots in Figure 2 show point estimates and 95% CIs for the primary efficacy outcome, 24 h PS, for individual trials of each drug, along with pooled FE and RE estimates and I-squared statistics.
Forest plots: change in average 24-hour pain score, direct comparisons with placebo.
Table 2 presents the results of the RE analyses of DLX vs. placebo. DLX was statistically significantly more effective than placebo on all three efficacy variables. The U-test was statistically significant (indicating the existence of treatment effects) for all efficacy outcomes and all tolerability outcomes except discontinuation due to other reason and diarrhoea. DLX resulted in significantly lower premature discontinuation due to lack of efficacy than placebo. Premature discontinuation due to adverse events was significantly more common for DLX than for placebo (NNH = 11 (95% CI: 7; 23)). Between-study variance (τ 2 ≠ 0) was detected for only two of the individual adverse event outcomes (diarrhoea and nausea). For the individual tolerability outcomes, DLX gave rise to a significantly higher incidence of dizziness, headache, nausea and somnolence than did placebo.
Random-effects pooled results: duloxetine vs. placebo.
Treatment effect (θ)
95% CI for θ
U-test
(p-value)
τ 2
NNT/NNH
Reduction in 24-hour pain intensity
(-1.364; -0.891)
<0.001
(0.628; 1.085)
5(3;7)
PGI
Tolerability
Premature study discontinuation due to:
- Lack of efficacy
- Adverse events
11 (7; 23)
(-0.636; 0.079)
θ is absolute difference for 24-hour pain intensity.
θ is log-odds ratio for Response, PGI and all tolerability analyses.
τ 2 is between-study heterogeneity.
NNT/NNH: Number needed to treat, number needed to harm. NNTs were calculated for response rate and NNHs were calculated for discontinuation due to adverse events.
Table 3 presents the results of the RE analyses of PGB vs. placebo. As for DLX, PGB was significantly more effective than placebo on all three efficacy variables. A significantly lower rate of premature discontinuation due to lack of efficacy was seen for PGB than for placebo. Premature discontinuation due to AEs occurred significantly more frequently for PGB than for placebo (NNH = 19 (95% CI: 10; 48)). Heterogeneity between PGB studies was observed for all efficacy variables and for diarrhoea and dizziness. PGB gave rise to a significantly higher incidence of dizziness and somnolence than did placebo.
Random-effects pooled results: pregabalin vs. placebo.
(0. 524; 1.155)
19 (10; 48)
Table 4 presents the results of the RE model for GBP vs. placebo. GBP was significantly superior to placebo for reduction in 24 h PS, the only efficacy outcome available in common for DLX and GBP. It was not possible to calculate an NNT for GBP, as binary responder rate data were unavailable. The incidence of dizziness and of somnolence was significantly greater for GBP than for placebo. For the remaining tolerability outcomes, no significant differences were found between GBP and placebo.
Random-effects pooled results: gabapentin vs. placebo.
63 (30; ∞)
θ is log-odds ratio for all tolerability analyses.
NNT/NNH: Number needed to treat, number needed to harm. * NNT was not calculated, due to absence of required binary data on responder rates. NNH was calculated for discontinuation due to adverse events.
Indirect comparison results
The results of the indirect comparisons between DLX and PGB are presented in Table 5. For the primary efficacy outcome, reduction in 24 h PS, a difference of -0.248 (95% CI: -0.667; 0.162) was seen in favour of DLX. Hence, DLX was not inferior to PGB on this outcome, as the upper bound of the confidence interval did not exceed the non-inferiority margin of +2 points. For response, the difference between DLX and PGB was close to zero and not significant. For the patient global impression (PGI-I/PGI-C) outcomes, PGB showed an improvement of 0.542 points over DLX, a difference that just reached significance (95% CI: 0.016; 1.060). DLX produced a significantly lower incidence of dizziness than did PGB, with δ = -1.084 (-1.903; -0.317). In the other tolerability comparisons (premature discontinuation, diarrhoea, headache, somnolence), no statistically significant differences were found.
Indirect comparison results: duloxetine vs. pregabalin.
Indirect treatment comparison (δ)
Mean (median)
95% CI for δ
Between-study variance (τ 2)
95% CI for τ 2
-0.248 (0.248)
(-0.667;0.162)
0.052 (0.024)
(0.001;0.252)
PGI-I/PGI-C
-0.251 (-0.235)
0.058 0.015)
δ is the mean difference in treatment effect between DLX and each comparator.
Table 6 presents the results from the indirect adjusted meta-analysis of DLX vs. GBP, in which no statistically significant differences were found.
Indirect comparison results: duloxetine vs. gabapentin.
This meta-analysis set out to compare the efficacy and tolerability of duloxetine, which is approved for the treatment of DPNP, with other drugs licensed or recommended in this indication. A variety of drugs, principally antidepressants, anticonvulsants and opioid analgesics, have been proposed for use in this difficult-to-treat condition. For example, controlled-release oxycodone has shown efficacy in diabetic painful neuropathy in two small trials [17, 18]. However, at present the only formally licensed agents for DPNP are duloxetine, gabapentin and pregabalin, while amitriptyline is unlicensed but recommended for DPNP. The intended comparators to duloxetine in this study were, therefore, the tricyclic antidepressant amitriptyline and the γ-aminobutyric acid (GABA) analogues gabapentin and pregabalin.
Our approach to selecting efficacy outcomes for pooling was stricter than some previous meta-analyses in neuropathic pain. A common metric for 24 h PS based on an 11-point ordinal scale was used in the trials of duloxetine, gabapentin and pregabalin in DPNP. This allowed us to use this outcome directly and to construct from it a measure of responder rate (proportion of patients achieving 50% pain reduction). In reviews of unlicensed drugs and neuropathic pain more generally, the lack of standardisation of outcome measures across trials has required a looser definition of response rate. Previous reviews [19–21] have reported NNTs based on the criterion of 50% pain reduction, but NNTs have also been derived from various pain scales or approximations made where data were not available. For consistency, we have reported similarly-derived NNT (and NNH) values for the placebo comparisons.
DLX was statistically superior to placebo for all three efficacy outcomes and for premature discontinuation due to lack of efficacy. Duloxetine gave rise to significantly greater incidences of dizziness, headache, nausea, somnolence and premature discontinuation due to adverse events. A similar pattern was seen with PGB, which was statistically superior to placebo for the three efficacy outcomes and for premature discontinuation due to lack of efficacy. PGB produced a significantly greater incidence of somnolence, dizziness and premature discontinuation due to adverse events. GBP was significantly superior to placebo in reducing 24 h PS and produced significantly greater scores for dizziness and somnolence than did placebo.
Our estimated NNT of 5 (95% CI: 3; 7) for the pooled studies of DLX compares with the NNTs reported elsewhere of 5.2 (95% CI: 3.7; 8.5) [22] and 4.1 (95% CI: 2.9; 7.2) [20], the latter estimate based on the first published trial of DLX [23]. Our estimated NNT for PGB (5 (95% CI: 4; 8)) was slightly higher than a previously reported value (4.2 (95% CI: 3.4; 5.4)) [24], due to our inclusion of studies DPN-149 and DPN-040. The NNTs for the individual PGB studies were very similar to those provided in a recent review [25]. Data on GBP were limited and did not provide information on treatment response. Recent reviews reported NNTs of 3.4 (95% CI: 2.1; 5.4) or 3.8 (95% CI: 3.4; 5.4) in DPNP for GBP [24, 26]. Otherwise, previous meta-analyses in neuropathic pain differ from the present study in indications and drugs studied, so are not directly comparable. Two reviews [20, 26] concluded that across the neuropathic conditions relieved by these agents, the tricyclic antidepressants (TCAs) appear to have the lowest NNT, at approximately 3, though as noted in the recent EFNS guidelines [22] the individual trials are invariably small, crossover studies that may overestimate the efficacy of TCAs.
Indirect adjusted comparisons were performed between DLX and PGB and between DLX and GBP, using placebo as the common comparator. Comparing DLX with PGB, only two comparisons reached significance: PGI-I/PGI-C, which favoured PGB, and the incidence of dizziness, which favoured DLX. In the comparisons between DLX and GBP, no statistically significant differences were detected.
Meta-analysis can be a powerful tool for comparing treatments across individual clinical trials, but caution is needed in its application and in the interpretation of results. We comment below on some limitations of the present study. The precision of the effect size estimated by meta-analysis depends in part upon the number of contributing trials and their size. Only in the last few years have formal clinical programs to support regulatory approval of drugs proposed for use in DPNP been carried out. This is reflected in the small number of trials that met the eligibility criteria for this meta-analysis.
In particular, the exclusion of amitriptyline from the meta-analysis warrants discussion as, along with other TCAs, it has been used in painful diabetic neuropathy for approximately 30 years. Although strong consensus exists for the clinical value of the TCAs, the clinical evidence stems from a series of small trials mainly conducted in the 1980s and 1990s, which were not designed to meet current regulatory requirements. As a result, relatively few studies met the formal criteria for inclusion in this meta-analysis. Among 20 articles describing the use of AMT in neuropathic pain, four were clinical trials of AMT monotherapy but only one of these, in which AMT and PGB were compared to placebo, met our pre-specified eligibility criteria. In that study, AMT achieved a numerically greater response rate than PGB. Of the two studies by Max, [27, 28] the earlier was a small crossover study with no washout period between AMT and placebo. The later study randomised subjects to one of two crossover comparisons: AMT vs. desipramine and fluoxetine vs. placebo. Twenty patients completed both comparisons but no direct comparison of AMT and placebo was reported. The studies by Max employed different pain measures from those used in the DLX, GBP and PGB studies. Moreover, benzotropine was used as an active placebo to mimic the anticholinergic side-effects of amitriptyline. This was designed to preserve blinding but precluded any tolerability comparison between AMT and no treatment.
Nevertheless, systematic reviews have reported NNT/NNH values for AMT and the TCAs as a class, based on various definitions of response. For example, Finnerup [20] reported a pooled NNT for the TCAs in peripheral pain of 2.3 (95% CI 2.1–2.7). McQuay[21] reported an NNT for AMT of 2.1 (95% CI 1.5–3.5), based on Max[28]. This was calculated from the 15 of 29 patients on AMT and 1 of 29 on placebo who reported "complete", "virtually complete" or "a lot of" relief. McQuay reported an NNT of 15.3 (95% CI 3.5–8) for fluoxetine, based on 22 of 46 patients on fluoxetine and 19 of 46 on placebo who achieved "complete", "a lot of" or "moderate" relief studied by Max [27]. The only trial involving AMT using the response rate criteria of our meta-analysis was the regulatory trial DPN-040 of pregabalin, which included AMT as an active control as well as placebo. The NNT for response for AMT compared to placebo in this study was 5, rather higher than reported elsewhere. Therefore, when comparing NNT values across studies, it should be recognised that these depend, inter alia, on the underlying definitions of response. The accepted convention in pain studies is to define the NNT as the number of patients needed to treat to obtain one patient with at least 50% pain relief, but obtaining this statistic may require some subjectivity. In our meta-analysis, the outcome of 24 h PS measured on an 11-point ordinal scale was available across all included trials, so responder rates based on at least 50% pain relief could be obtained in a consistent manner. In other studies, various categorical scales have been used and judgement is required as to which levels of response correspond to 50% or greater pain relief. While we acknowledge that inclusion of AMT would have been desirable in view of the consensus for its clinical value and its widespread use in DPNP, the above data constraints precluded that possibility for this particular study.
Although opioids were excluded from this meta-analysis, as none is licensed in painful diabetic neuropathy, oxycodone has been shown to be effective in this indication in two randomized, placebo-controlled trials [17, 18]. European guidelines [22] report a combined NNT for these trials of 2.6 (95% CI 1.9–4.1), though they warn that the eligibility of prior opioid users may have exaggerated the response rate.
Only two small studies of GBP were eligible. The three studies of DLX and six studies of PGB involved more patients, reflecting that these were trials designed to meet regulatory authorities' requirements. Pooled estimates from small numbers of trials may gain little in precision over estimates from the individual trials. This is not necessarily a concern where trials are large and adequately powered, where differences in effect sizes are large, or both. However, the two studies of GBP contributed only 114 patients on active drug, and pooling them produced only modest shrinkage in the confidence intervals. Moreover, concerns have been expressed that small studies tend to suffer from design shortcomings, such that they over-estimate effect size [29]. It was not possible to calculate an NNT for GBP. Therefore, we believe that the most important and valid results in this study are the direct comparisons of DLX and PGB with placebo and the indirect comparisons between DLX and PGB. Investigating the validity of indirect adjusted comparisons, Song [30] found that the results of indirect comparisons usually, but not always, agree with results from head-to-head randomised clinical trials, and concluded that in the absence of direct evidence, adjusted indirect comparisons may provide useful information.
The possibility of study selection bias is a potential threat to the validity of meta-analyses. For DLX and PGB, we are confident that all studies in DPNP were identified, and that selection bias was therefore unlikely. As of the date the literature search was performed, the manufacturer provided study reports of all completed trials of DLX, none of which had been published. The three eligible trials of DLX have since been published [23, 31, 32]. No relevant trials have been conducted since the time of the search. We did not contact the manufacturer of PGB and GBP to identify unpublished studies, as we considered that all relevant evidence would have been disclosed to the FDA and EMEA, whose drug assessments are in the public domain. The European Public Assessment Report, which was published in December 2004, only one month prior to our literature search, stated that it included all six completed trials of PGB in DPNP. Two of these six trials had been published at the time of search[15, 16], and a further three [33–35] had been published as of October 2008. The apparently unpublished study is DPN-040, which included AMT as an active comparator. All six studies we identified, along with a recently completed seventh trial [36] not revealed by our search, have recently been the subject of an article [37] reviewing dose response to PGB. For GBP, which is a patent-expired drug, it is unlikely that any recent (unpublished) manufacturer-sponsored trials have been conducted.
The systematic review process to determine study eligibility appears to have resulted in a reasonably homogeneous selection. Trial designs shared many common features, outcome metrics and patient characteristics (except for gender and proportion with type 2 diabetes), and we detected little evidence of overall heterogeneity between the trials included. With respect to the between-study variability in outcomes for each drug, there were no significant differences, but we conservatively chose to report RE as well as FE models in the drug vs. placebo comparisons.
To demonstrate the equivalence of two drugs, it is common practice to perform tests of non-inferiority. In the context of DPNP, 24 h PS is the only efficacy outcome for which a clinically meaningful non-inferiority margin has been documented, based on the work of Farrar [8], who proposed a margin of two points on the 11-point pain intensity rating scale. However, it was unnecessary to invoke this non-inferiority margin in the comparisons of DLX with PGB and GBP. Using the stricter criterion of equivalence, there was no difference in the 24 h PS scores between DLX and each of these comparator drugs, and we conclude that DLX is equivalent to GBP and PGB on this outcome. Although PGB showed a statistically greater score than DLX on the PGI-I/PGI-C outcome, it is not clear that the measured difference of approximately 0.5 points is clinically meaningful. This categorical seven-point scale describes "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse" and "very much worse". Intuitively, it is difficult to conclude that less than a whole interval change on this scale is meaningful. If a whole interval were accepted as the non-inferiority margin, DLX would be non-inferior to PGB in terms of patients' global impressions.
The indirect comparisons of tolerability were, by definition, limited to those outcomes for which data were reported in common for each comparator. One outcome for which a comparison was not possible in this study was weight gain. The European Public Assessment Report refers to dose-related weight gain with PGB (2.4–8.2% of patients), compared to 0.8% of placebo-treated patients, over all neuropathic pain indications. Among DPNP patients for whom data were available, the mean weight gain over the assessment period was 1.6 kg for PGB-treated patients and 0.3 kg for placebo-treated patients. In the Integrated Safety Summary for DLX in diabetic neuropathic pain, DLX did not differ significantly from routine care or placebo controls in the incidence of weight gain.
Based on the pooling of common outcomes measured in randomized, controlled trials, we conclude that duloxetine is comparably effective and tolerable in the treatment of diabetic peripheral neuropathic pain to two anticonvulsants, gabapentin and pregabalin, which are pharmacologically unrelated to duloxetine. The summary reporting of trial results tends to conceal that response and tolerability to the various types of pharmacological treatment may be highly individual. In neuropathic pain, the empirical approach to treatment and the common use of off-label treatments attest to the clinical need for a wide range of drug choices. This study suggests that duloxetine may offer a valuable, additional option for this disabling condition.
The study was sponsored by Eli Lilly and Company, which provided internal study reports of all controlled trials of duloxetine in DPNP, and Boehringer Ingelheim International GmbH.
12883_2008_220_MOESM1_ESM.pdf Authors' original file for figure 1
12883_2008_220_MOESM3_ESM.bmp Authors' original file for figure 3
TKL and AG-C are employees of Eli Lilly and Company and BM is an employee of Boehringer Ingelheim. These two companies market duloxetine, which is indicated for DPNP, in the European Union. Eli Lilly and Company reimbursed i3 Innovus for payment of the Journal's article processing charge. JC is a current employee, and SQ is a former employee, of i3 Innovus, a business unit of Ingenix Pharmaceutical Services Limited, which carried out the study reported here under a commercial contract with Eli Lilly and Company. ML is a former employee of Innovus Research (UK) Ltd, which was acquired by Ingenix in 2006. Funding was not contingent upon publication of the manuscript. GS and DS have received fees as occasional advisors to Eli Lilly and Company and DS has received financial support from Lilly to conduct a pilot study on the determinants of diabetes-related complications. None of the authors hold stocks or shares in Eli Lilly and Company or Boehringer Ingelheim, the latter company being privately owned. No patents have been applied for relating to the content of the manuscript. None of the authors has any other financial or non-financial competing interests.
The systematic review, the selection of included studies and outcome measures, analysis or reporting of results were performed entirely independently by those authors who are (JC) or were (SQ, ML) employees of i3 Innovus or Innovus Research (UK) Ltd. Protocols for the systematic review and meta-analyses were developed by i3 Innovus (ML), reviewed and commented on by all authors, and amendments were made based on the recommendations of Professors Simon and Said. The systematic review (ML), analyses (SQ) and manuscript preparation (JC) were performed by i3 Innovus; the manuscript was reviewed and agreed by all co-authors.
Health Economics & Outcomes Research, i3 Innovus, Uxbridge, UK
Innovus Research (UK) Ltd, High Wycombe, UK
Service de Diabétologie, Hôpital de la Pitié, Paris, France
Service de Neurologie, Hôpital le Kremlin Bicêtre, Paris, France
Global Health Outcomes, Eli Lilly and Company, Indianapolis, IN, USA
European Health Outcomes, Eli Lilly and Company Limited, Windlesham, Surrey, UK
Global Health Economics & Outcomes Research, Boehringer Ingelheim GmbH, Ingelheim, Germany
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Great British Bake Off
What made Hercule Poirot perfect
Agatha Christie's Belgian detective was a brilliant creation, brought to life by David Suchet's sublime acting
Though classically trained, David Suchet has never adapted a de haut en bas attitude towards playing a television detective Photo: REX
By Laura Thompson
It is almost 25 years since the detective Hercule Poirot, created by Agatha Christie and played by David Suchet, made his debut on ITV. The first of 70 episodes of Agatha Christie's Poirot, a minor short story called The Adventure of the Clapham Cook, was broadcast in January 1989. Tonight, Curtain – Poirot's Last Case brings this long televisual life to an end.
Even those who view the Christie oeuvre as irredeemably lightweight may feel a sense of momentousness, a tug of poignancy, at the death of a character who has been part of our national life for a generation.
For Suchet, who at the age of 67 has moved through his middle years hand-in-hand with the bumptious Belgian, the wrench is tremendous. A highly distinguished stage actor, an interpreter of Shakespeare, O'Neill and Miller, Suchet has never adapted a de haut en bas attitude towards playing a television detective. Sensibly and graciously, he has only ever expressed extreme gratitude to the part. He also has great fondness for Poirot, rather as for an annoying but essentially lovable relation; he asked to film another episode after Curtain was completed, in order to leave Poirot suspended forever, in his mind, in a state of buoyant health.
Agatha Christie was more robust in her attitude. Having created the character, she was also willing to kill him off. There is a tantalising possibility that the television version will differ in this respect, but the plot of Curtain, the novel, demanded that Poirot should die.
It is that kind of book: melancholic, comfortless, suffused with an irresolute despair about the evil that floats so easily to the surface of people. Almost everybody in the novel judges another person to be supremely dispensable, and believes that the world would be better without them. That is strong stuff, realistic to the point of cynicism. It is a very long way from the received opinion of Christie, that she wrote only "animated algebra" and had scant grasp of human nature. So it is fortunate that Curtain has been adapted for television by the best of the Poirot screenwriters, Kevin Elyot, who divines the twisting roots that underpin Christie's precise, translucent structures.
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Curtain was completed 35 years before its publication in September 1975, when it generated the famous Poirot "obituary" in the New York Times. The idea had been to publish posthumously but, as the frail Christie had no book for her public that year, and was anyway just four months from her own death, Curtain made its premature and sensational appearance.
Christie had written the book in 1940, aged nearly 50, when she was working as a dispenser at University College Hospital, dodging the bombs that had flattened her Kensington house and, as she thought, liable to die at any minute. This precarious existence infected Curtain with a powerful sense of uncertainty. It also made Christie compulsively active. She wrote like a fiend, producing some of her finest books.
Living alone in London – Max Mallowan, her husband, had been posted to North Africa – she attended a great deal of theatre and wrote excitable, perceptive letters to her husband about Shakespeare. The character of Iago, in particular, obsessed her. She analysed his motivation as if he were a real person, imagining his joy at "seeing Othello suffer as he has suffered". Motive, with Christie, was always what mattered. The idea for the plot of Curtain came, I strongly suspect, from these musings on Iago.
What is usually said is that she wrote the book because she was heartily sick of Poirot and had found a plausible way to get rid of him; only the horrified wails of her publisher persuaded her that the moustachioed cash-cow must live.
This is nonsense, of course. The novel was by way of being an insurance policy. She stashed it away for her daughter Rosalind, as a means to generate some income if she, Christie, succumbed to a German bomb. Furthermore, as Christie's biographer, I read hundreds of her letters and notes, and I found not one reference to her fabled dislike for Poirot. On the contrary, she treated him with intense protectiveness.
She brought him to life almost 100 years ago, in 1916, when she was inspired to write her first crime novel, The Mysterious Affair at Styles. She was unable to account for the creation of this extraordinary little being, with his fanatical love of order, his delicious conceit, his sexless cosmopolitan charm. In her autobiography she referred, almost cursorily, to how Poirot was inspired by the wartime Belgian refugees who had lived in her home town of Torquay: "I settled on a Belgian detective… Hercule – Hercule Poirot. That was all right – settled, thank goodness." But this was no explanation of the mystery of creativity, the instinct that had guided her so surely.
In a sense, Poirot is merely a fabulous line drawing, an accumulation of idiosyncrasies: the moustaches, the meticulousness, the little grey cells. Yet from the moment of his irruption on to the page ("Mon ami Hastings!"), he is vividly alive, possessing that indefinable literary quality of connection with the reader.
What he is, too, is pure detective, in a way that comparable creations are not. Dorothy L Sayers gave us Lord Peter Wimsey, an intellectual giant and too attractive for words; P D James gave us Adam Dalgleish, a poet to rival Auden: these men are too good to be detectives, too good for the genre that they inhabit.
Not so Poirot. He has no inner life as such, only a supreme clarity of mind, a worldly grasp of sin and a utilitarian, bourgeois morality. "I do not approve of murder," is his mantra. He is content to remain within the world of geometry and omniscience. Thus he has become a kind of template: infinitely consoling, oddly mythical.
Partly because of this rootless, ageless, almost bodiless quality of Poirot, Christie was always intensely reluctant to have him played by an actor. Onstage, in her 1930 play Black Coffee (the only Poirot property not to have been performed by David Suchet), he was portrayed by Charles Laughton, which was high-end but terrible casting.
Later the part was taken by Christie's friend Francis Sullivan, who would pester her atrociously about playing Poirot on screen. She hated the idea, but not as much as she hated the 1964 film The Alphabet Murders, starring an insanely miscast Tony Randall. "I don't suppose," she wrote to her agent, "there could be any misery greater for an author than to see their characters completely distorted."
After this Christie pulled up the drawbridge, despite huge financial inducements, allowing Poirot only to appear on American radio. Not until 1974 did she permit another screen adaptation, the superb Murder on the Orient Express, in which Poirot was played by Albert Finney. Although rather wonderful, Finney was wildly wrong. So, too, was Peter Ustinov in the 1978 film Death on the Nile; yet to my mind he caught something of the spirit of the character, infusing Poirot lightly with his own droll intelligence.
Nevertheless, it is Suchet, of course, who has come to define Hercule Poirot. His conception, which is faithful to Christie's novels yet very much an actor's creation, has developed astonishingly, although his English grammar has never quite made the grade.
It has taken Poirot from a semi-comical dandy, with a shiny Art Deco apartment and a bombastic pleasure in his own brains, to a dark, heavy-eyed figure tormented by the moral implications of a life spent dealing in guilt and innocence. Over the past decade or so, as the Poirot adaptations began to plumb Christie's hidden depths, so Suchet has gathered together the formidable power of his classical training and turned it squarely on to Poirot. It is a fabulous performance, no question: an achievement unlike any other.
Whether the works of Agatha Christie can quite bear the Wagnerian weight of this final series, I am not sure, but in a sense this has ceased to matter. The last days of Hercule Poirot have taken on their own importance, as if he had a life outside his creator. As, indeed, he now does.
And it is an eternal life. Those unduly distressed by tonight's events can always turn to ITV3 tomorrow evening, when a 1993 adaptation is being screened of a short story called The Underdog, and where the black moustaches will merrily twitch once more.
Laura Thompson is the author of 'Agatha Christie: An English Mystery'
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Here's a cute Carroll-related comic by talented cartoonist Bill Amend, forwarded by one of our mimsy minions. Enjoy! And if you would like to see more of the Foxtrot comic, click me.


Goal: Demonstrate the use of collaborative tools. A collection of evidence: establishing and use of social networking, managing files and documents, and experience with "cloud computing" will be placed in the Digital Portfolio. This project will include a critique of an online tool for use in the classroom setting.
Platform: Use an online presentation tool- Google presentation, Haiku Deck, Prezi, Video, Screencast…must be uploaded to online location (Dropbox, Vimeo, TeacherTube, etc).
You will randomly be given a tool to research. Click the link to your "assigned" collaborative tool.
Find a video about the tool or create your own on how to use this tool.
In an online Presentation, what do you see as pros and cons for the tool, cost, Mobile Device compatibility, and have an idea of how it could be used in the classroom. Can more than one student contribute to this tool?
Remember to submit your assignment into the appropriate SAKAI assignment page and embed the link into your own digital LiveBinder portfolio.


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Home » Fellows & Distinguished Visitors » Anne Applebaum
Photo: Annette Hornischer
Columnist and Journalist, The Washington Post
George Herbert Walker Bush/Axel Springer Fellow - Class of Fall 2006 and Class of Fall 2008
Anne Applebaum is a columnist for the Washington Post and Slate, covering US and international politics, and the political director of the Legatum Institute in London. She writes regularly for a range of publications in Britain and the US, including the New York Review of Books, New Republic, Spectator, and the Daily Telegraph. She has given lectures at Yale, Columbia, Heidelberg, and Humboldt Universities, among many others, and has received fellowships from the National Endowment for the Humanities, the Hoover Institute and the American Academy in Berlin. Her book Gulag: A History, which narrates the history of the Soviet concentration camp system, won the 2004 Pulitzer Prize for nonfiction and has appeared in more than two dozen translations.
Formerly a member of the Washington Post editorial board, Applebaum has also worked as the foreign and deputy editor of the Spectator, as the political editor and columnist for the Evening Standard, and as the Warsaw correspondent for the Economist. She graduated from Yale University in 1986, has a master's degree from the London School of Economics and studied at St. Antony's College, Oxford, as a Marshall Scholar. Her husband, Radoslaw Sikorski, is the foreign minister of Poland.
The Anti-Civilization: How Central Europe was Transformed, 1945-1956


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NIAGARA PENINSULA CONSERVATION AUTHORITYBALL'S FALLS JANUARY 18, 2012 7:45 p.m.MEMBERS PRESENT:MEMBERS ABSENT:STAFF PRESENT:B. Maves (Chairman)D. BarrickB. BatyS. BeattieT. DalimonteC. D'AngeloD. DiFruscioT. EastonD. EkeA. JeffsD JoynerB. Timms(Vice-Chairman)D. Ransom (with regrets)B. Sharpe (with regrets)B. Steckley (with regrets)T. D'Amario, CAO/Secretary-TreasurerD. Bois, Acting Recording SecretaryJ. Kukalis, Director, Water ManagementD. Baker, Director, Land ManagementM. Stack, Director CommunicationsOTHERS PRESENT:BUSINESS:Don Pearson, General Manager, Conservation OntarioJohn Crossingham, SolicitorRandy Momot, MacGillivray PartnersMark Neufeld, Chairman Source Protection CommitteeAndy Fevez, Past NPCA Board MemberDave Drobitch, Superintendent, Long Beach & Chippawa CreekDoug Durant, DSBN, Manager of Projects & MaintenanceColleen Fast, DSBN, StaffKevin Graham, DSBN, StaffGreg A. Redden, Macdonald Zuberec Ensslen Architects Inc.Harald Ensslen, Macdonald Zuberec Ensslen Architects Inc.Frank Scremin – Hamilton Int. Airport, Director, OperationsEric Cunningham – Hamilton Int. Airport, CommunicationsKlara Young-Chin, Friends of One Mile CreekGerry Beneteau, Friends of One Mile CreekJohn Sonneveld, Wainfleet CitizenGlen Robins, Wainfleet CitizenBev Lepard, Wainfleet CitizenLen Pennachetti, Twenty Valley Tourism / Cave Spring CellarsEric Cunningham, Former MPP (1977-1984)The Chairman called the meeting to order at 7:45 p.m., welcomed all in attendance and requestedanyone who had a conflict of interest to declare it.


I have liked the Lester Young small group recordings that I have heard. My introduction came with the four-LP Pablo series, Lester Young in Washington DC, 1956. These recordings were made toward the end of Young's life and contain some of his most ethereal playing.
I suppose I am also a child of the 1970s and prefer high fidelity to high history. These small group recordings have a better sonic quality than Young's Columbia recordings with Count Basie in the 30s. At any rate, the release of all of Lester Young's recordings with the Oscar Peterson Trio on compact disc interested me.
This reissue is made up of performances recorded November 28, 1952 and released on four separate releases: Lester Young With the Oscar Peterson Trio Volumes 1 and 2, The President, and The President Plays with the Oscar Peterson Trio (compact disc, providing only "It Takes Two to Tango"). There is one unissued track, the throw-off 52 second false start of "I Can't Get Started".
All of Young's performances are transplanted from a different era. These recordings were made a mere three years before Charlie Parker's death. The harmonic advances of Be-bop had already been introduced and assimilated into the Jazz vernacular by this time. Yet Young, while adopting (or pioneering') some Bebop practices, remains a melodic, horizontal performer, in sharp contrast to the harmonic, vertical performers of classic Be-bop.
To my baby-boomer ears, Young's performances do not sound so much old > fashioned as they do archival. Like his personality, Young's playing is wispy, understated, and very, very clever. Listening to Lester Young, I react the same way as I do when I listen to Dave McKenna or Ralph Sutton. I honor these men for their place in the evolution of Jazz. But their immediacy is more of a Louis Armstrong / Joe Oliver variety than of a Charlie Parker / Dizzy Gillespie variety.
The Oscar Peterson Trio provides a hand in glove accompaniment for Young on these recordings. Oscar Peterson, who is very much in the mold of Art Tatum (a true contemporary of Young), is very comfortable with Young's variety of playing. The Trio is made up of Peterson, Ray Brown (bass), Barney Kessel (guitar), and J.C. Heard (drums).
The songs included in this collection are part of the standard Young repertoire. "Tea for Two", "On the Sunny Side of the Street", and "Stardust" are all performed with the characteristic grace associated with Young. The real fun on this record is the mildly pornographic"(It Takes) Two to Tango" where Young performs both as vocalist and soloist. The rhythm section supports Young superbly. The recordings are quite acceptable; my only quibble would be the bass and piano are muddied in the remastering. As for Young's tenor, it is so exquisite the listener can hear his breath expel as he plays a particularly breathy part.
I recommend this record for small combo enthusiasts who want to hear a singular personality that precedes the ubiquitous Be-bop and Hard Bop of the past thirty years.
Track Listing: Ad Lib Blues; I Can't Get Started; Just You, Just Me; Almost Like Being in Love; Tea for Two; There Will Never Be Another You; (Back Home Again in) Indiana; On the Sunny Side of the Street; Star Dust; I?m Confessin';; I Can't Give You Anything But Love; These Foolish Things; (It Takes) Two to Tango; I Can't Get Started (False Start).
Personnel: Lester Young: tenor saxophone, vocals; Oscar Peterson: piano; Barney Kessel: guitar; Ray Brown: bass; J.C. Heard: drums.


We have relationships with investigators throughout Pennsylvania (PA), from the capital city of Harrisburg to every major city and metropolitan area. We accept expert cases, including court appointed. Be sure and contact our office to learn how we can help you.


This is the homepage for Fantasy Flight Games Organized Play Nordic Championships. The championships take place once a year and are held for the following games: A Game of Thrones LCG, Armada, Imperial Assault, Netrunner LCG, Star Wars the Card Game, Warhammer 40 000: Conquest LCG and X-Wing Miniatures Game. Each year a new venue and this homepage aims to gather all info about them, so check back often.
Hi there, my name is oli and I'm from the UK.
I'd like to register but need to sort out a method of bank transfer. Any help ?
Absolutely! What event (Stockholm or Uppsala) do you want to register to?


text:
Bridging Traditions: Idealism and Pragmatism
Even though the pragmatists, both classical and contemporary, have been attentive readers of various figures in the idealist tradition, their views are normally read in opposition to what an idealist approach to philosophy is supposed to entail. Thus, it is hard to deny that Charles S. Peirce studied in depth Kant when he was a young scholar, or that Hegel was an influence on the young John Dewey. As far as contemporary pragmatists are concerned, figures like Hilary Putnam and Robert Brandom have certainly not neglected to consider some of the idealists' ideas.
This circumstance notwithstanding, pragmatism and idealism have been normally set against each other. Of course there seems to be plenty of reasons to do so. First of all there are methodological reasons. Pragmatists normally propose an approach to philosophy that is in continuity with the sciences and that attacks a priori methods of arguing. Accordingly, they endorse a radical form of fallibilism and leave behind the search for ultimate truths. This seems to be deeply in contrast to many idealists, who certainly used a priori lines of reasoning and aimed to attain certain and stable knowledge. There are also theoretical reasons. For example, many pragmatists (of course with important differences among them) could be seen as endorsing a peculiar form of naturalism, where the human mind is seen as being in continuity with nature, while not being reduced to very basic forms of explanation. On the other hand, idealist approaches to philosophy are normally read in opposition to naturalistic points of view, insofar as they give priority to the mind and to the way in which it offers us the possibility to represent nature in the first place.
There are various reasons to question this rigid opposition. The Frankfurt conference will thus show that idealism and pragmatism have a lot in common. Just to mention some examples, Charles Peirce was surely critical of the a priori method used by the rationalists and by Kant, but he also continued to use some a priori lines of reasoning in his mathematical and logical inquiries. These inquiries provided the basic ideas for his entire philosophy. Moreover, Clarence I. Lewis, another important figure in the classical tradition of pragmatism, developed a new account of the a priori method, which he called the "pragmatic a priori". This is only to show that the a priori method was not simply rejected by the pragmatists. Rather, some of the pragmatists tried to reinvent this method in a new framework. On the other hand, the recourse to a priori lines of reasoning or to a priori sets of concepts has been understood in very different ways in the idealist traditions. Thus, the way in which Hegel placed a priori concepts in an historical developmental framework can be associated to some pragmatist way of describing the evolution of thought. As far as naturalism is concerned, it is important to keep in mind that the kind of naturalism endorsed by the pragmatists was of a very peculiar kind. In fact, they have not ever tried to reduce mental phenomena to more basic kinds of explanation. They have only tried to read those phenomena as being in continuity with natural processes. In their form of naturalism, the pragmatists allow thus room for the kind of mental phenomena that are considered the starting points of the idealists. Moreover the pragmatists would surely agree with the idealists in saying that our thought plays an essential role in the production of our very own representation of nature.
There are so many reasons to question the customary opposition between pragmatism and idealism.The conference results from an international collaboration in which two different projects are conjoined: 1) A project on 'Pragmatism, Kant and Transcendental Philosophy' that Gabriele Gava is carrying out in Frankfurt as a research fellow of the Humboldt-Stiftung, and 2) A project on 'Idealism and Pragmatism: Convergence or Contestation?', sponsored by a grant of the Leverhulme Trust and lead by Robert Stern from the University of Sheffield. The first two days of the conference, sponsored by the Deutsche Forschungsgemeinschaft, will be connected to the first project and will be dedicated to the relationship between pragmatism, Kant and transcendental philosophy, while the third day, which is part of the second project, will consist of a workshop exploring the connections between pragmatism and idealism in the fields of metaphysics, epistemology, logic and language.
Confirmed speakers (December 3, 2013):
James Conant (Chicago)
Alfredo Ferrarin (Pisa)
Sebastian Gardner (UCL)
Gabriele Gava (Frankfurt)
Daniel Herbert (Sheffield)
Christopher Hookway (Sheffield)
Wolfgang Kuhlmann (RWTH Aachen)
Catherine Legg (Waikato)
David MacArthur (Sydney)
Marcel Niquet (Frankfurt and Ceará)
James O'Shea (UCD)
Sami Pihlström (Helsinki Collegium for Advanced Studies)
Sebastian Rödl (Leipzig)
Robert Stern (Sheffield)
Marcus Willaschek (Frankfurt)
Eisenhower Saal (Raum 1.314), IG-Hochhaus, Campus Westend, Goethe-Universität, Grüneburgplatz 1, Frankfurt am Main
Conference site
Pragmatism, Idealism
Dec 03, 2013, 19:28 by Mats Bergman


I've been taking surveys of the readership of this weblog since 2004. Here is my last one, from the summer of 2010. Before I moved to Discover I also did one in the winter of 2010. Here's a reader survey from the winter of 2009. Another from 2005.
I set up a survey with a new service this time. I did integrate some of the suggestions of commenters as well. One difference between this survey and previous ones is that I have a lot more free-form text boxes with numeric answers. So you give your specific age or income, instead of selecting from a category. The survey shouldn't take more than ~5 minutes, as many of the questions are yes/no, or very simple, such as your highest education attained.
I'll post the first results within 24 hours, and probably post the raw files at some point in the near future if you want to crunch them yourself. I set it up so it goes from banal demographic questions in the beginning to more detailed and somewhat esoteric queries by the end. None of the questions are mandatory.
You can complete the survey at this link: http://questionpro.com/t/ACQlIZK0wT.
Update: Might as well point you to the early results (the "open-ended" results aren't there, I'll have to format that for later).
Some comments on the survey, which I just filled out.
1) The series of questions about biologically determined behavior. This is poorly worded, though I'm not sure how to correct this. I answered 3 questions (which I could not then change to no answer without abandoning the survey), and then realized that I was reading "Biologically determined" as "genetically determined". Once I realized this, and also realized that I could not change the filled answers to blanks, I was stymied.
1a) Sleep is a biological phenomenon, and heavily determines behavior, not just the difference in behavior between periods of being awake and being asleep. When awake, behavior depends on the quality of sleep, the need for sleep, whether there is a possibility of napping soon, etc.
1b) More to the point: hunger is a biological phenomenon, both short term (I'm hungry NOW; feed me!) and long term (famine) heavily influence behavior (in re its short term effects: my wife gets phenomenally crabby when hungry but is generally otherwise very sweet and well behaved). Both types of hunger are also social phenomenon: short term due to, e.g., fads about dieting: long term due to all the sorts of things that Amartya Sen has identified about modern famines (at least since the 19thC Irish famine) being due less to total availability of food and more to its distribution and allocation.
1c) In its biochemical aspects, stress is a biological phenomenon. Parenting is generally considered a social phenomenon, but it can have consequences for how stress is experienced, especially by the child but also the parent.
1d) This is more generally true of a variety of social phenomena, essentially genes mediating environment. I'm pretty confident that you have expressed this POV, although I doubt I could quickly find it in your posts.
1e) I believe that the questions could have been better worded so that those taking the survey could determine what you were getting at, and then be sure of correctly answering about their opinion on that position. As it is, I think you will get some heterogeneity in the answers as to what respondents thought they were being asked about. Yeah, this is true about most opinion surveys, people are responding to widely used phrases without the surveyors being sure that all or even most are attributing similar meaning to the phrases, but this is generally considered a bug, not a feature (except perhaps in marketing, where all you care about is the emotional resonance of the phrase).
*Yes, his. In my experience, fathers feel and express similar sentiments much more often than mothers.
You might want to clarify the question about economic liberalism. Does 'liberal' there mean 'leftist', i.e. favour restrictive policies, or does it mean 'liberalist', i.e. lassez-faire?
Just on the first page – can you expand the possible sexual orientations? You've been pretty exclusive with just those three.
I agree that the choice of the term "liberal" to describe economic ideology is ambiguous. Many in Europe, and current Marxists in their disparagement of "neo-liberalism" still use the term in its 19th century "classical" liberalism sense to describe non-mercantilist free market policies whereas in the United States it connotes active government participation in directing the economy.
Odd early results. Only 20% have taken an intro calculus class but tons of doctorates and college degrees.
i think paul has to be right. i should have made it more explicit?
#5, you're right. though most people understood it when i checked by crossing with tax rates.
a mode for "biologically derived behavioral differences within a coherent population (e.g., Chinese) is "somewhat significant" yet a mode for "biologically derived behavioral differences between the human races (e.g., East Asian vs. European)" is "very modest".
intra vs. inter population variance. is the variation in shyness greater amongst chinese or between chinese and europeans?
Wow. Left a lot blank this year. Do people really remember their Myers-Briggs personality type?
I missed the genetic vs. biological distinction too that (1) mentioned. I should have caught that.


The National Statistics Institute has started the project "Support for implementation of profiling activities in the Member States", according to the European Commission grant agreement № 831427–2018–BG–Profiling.
• implement updated European profiling and increase the data quality of multinational enterprise group in EuroGroup register. NSI of Bulgaria will participate in work on European profiling as country of global decision centre (GDC) and partnering exercise on foreign groups for the reference year 2018.
• test the feasibility to produce an initial EuroGroup global frame for 2018 reference year, which to be backbone of foreign affiliate trade statistic, increase the collaboration between national statistical business registers and EuroGroup register with foreign affiliate trade statistic users for scope and data preparation.
The project duration is 12 months and will be completed at the end of December 2019.


text:
The Game Changer 3rd February 2015
The March issues are on the shelves and the SS15 campaigns are out, but this season the game has changed and it's a big talking point for the fashion industry.
The biggest change this season comes from the power of social media. For years the big publication houses have been the choice for brands to launch their seasonal advertising campaigns, and quiet rightly, the likes of Vogue and Harpers Bazaar boast a readership of more than a million in the UK, great, once upon a time.
However, with celebrities now commanding a social media following hitting the millions, not even Vogue can compete. The power of celebrity isn't something new either! Vogue Paris featured Audrey Hepburn on its cover back in 1962.
If the aim is to get the brand out to the masses then you need to get a celebrity to launch it, and this has happened more than once this season. A clever idea in sharing this content couldn't now be easier, and the 'like' button is merely a click away.
So who is tapping into the craze? Well of course Kim and Kanye (West, just in case you have been in the Amazon Jungle for a while) for Balmain kicked off a social frenzy in December 2014, launching four images on Kim's own Instagram page, reaching a staggering 24.9 million followers.
Celine followed suit this month and released the image of author Joan Didion in a dark glasses and polo neck for its 2015 campaign and the world couldn't ignore it, and before you say it's just for the fashion followers everyone from the Guardian, New York Times and Forbes featured it.
And Celine wasn't the only brand to kick start the New Year with its new releases, Calvin Klein also worked with Justin Bieber to become the face of the SS15 campaign and again, it was Justin who was responsible for launching the images. So seven images and one video later and 22million people round the world have the campaign in their hands.
It's almost a no brainer, but models should fear not…just yet. The power of Cara Delevingne still has a reach of nine million and Jourdan Dunn one million. True to the fashion world, the trend is changing but like most things, it's likely to come back around. Now over to the publication houses to raise their game.
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27/11 - Branch Transformation: Do you really need a branch of the future? And does it have to be a Ferrari?
05/11 - Ethos crowned Food Shop of the year
02/11 - Sartorial excellence versus the 'hard sell'
30/09 - Telling a brand new story
23/09 - Changing London fashion
21/08 - Let them eat cake
11/08 - Soaking up style in Scandinavia
24/07 - Jabba II lives
13/07 - Thoughts from the inside
09/07 - The last days of 'Jabba' the hut
07/07 - Ethos founder recognised for achievements
30/06 - A very moving experience
30/06 - Finding your starter for ten
24/06 - I-AM proves the 'model' agency
23/06 - It's a Pitti we had to leave
18/06 - I-AM Commended for Ethos Project
18/06 - I have too many bikes. Said no cyclist ever!
11/06 - News from I-AM Sessions
08/06 - Running with a Great Partner
06/05 - Omni-Channel Brand Identity Design in Banking
18/03 - Can Fast Food be Premium?
03/03 - In Interview with Best Banking – Technology could evoke a renaissance in banking
18/02 - You've got to have Sole
03/02 - The Game Changer
29/01 - I-AM supports a desert marathon runner- Go Go Go!!
26/01 - The Importance of Brand Behaviour


text:
Trump 2020 Landslide
Crisis Reports
Fireworks: Former ICE Acting Director Homan BLASTS Dem rep during hearing for besmirching his character and calling him a racist (Video)
By Jon Dougherty
(NationalSentinel) A fiery exchange occurred Friday during a House hearing on Capitol Hill between former ICE Acting Director Thomas Homan and Rep. Jesus Garcia (D-Ill.) after the latter questioned the career civil servant's integrity and flat-out called him a racist for defending ICE and Border Patrol agents as they continue to deal with a massive influx of migrants at the border.
"Mr. Homan, I'm a father. Do you have children? How can you possibly allow this to happen under your watch?" Garcia began, referring to the unfortunate deaths of some migrant children and others when Homan was leading his agency.
"Do you not care? Is it because these children don't look like children that are around you? I don't get it. Have you ever held a deceased child in your arms?" Garcia continued.
After staring at Garcia in disbelief for a few pregnant pauses, Homan shot back, "First of all, your comments are disgusting."
At that, Garcia attempted to interject that he thought the same of Homan's comments, but the former ICE acting director was having none of it.
"I've served my country for 34 years," Homan said, signaling to the committee chairman that "this is getting out of control."
Through crosstalk, Homan added:
I've served my country for 34 years, and yes, I held a five-year-old in my arms in the back [of a] tractor-trailer. I knelt down beside him and said a prayer because for him because I knew what the last 30 minutes of his life was like (in a sweltering hot rig).Â
And I had a five-year-old son at the time. What I've been trying to do, my 34 years serving my nation , is to save lives. So for you to sit there and insult my integrity and my love for my country and for children…that's why this whole thing needs to be fixed. And your the member! Fix it!
Following the interview, Homan appeared on the Fox Business Network with host Gregg Jarrett to discuss the exchange, which he called "appalling."
Noting that Garcia accused Homan "of being racist, which is what uninformed people do when they don't have a good argument," Jarrett asked Homan how many lives Border Patrol agents have saved.
"Just over the last year four thousand lives," Homan said, "but nobody wanted to talk about that today. I was the only one who wanted to talk about it."
Homan also blasted Rep. Gerald Connolly (D-Va.) as a "coward" for "throwing dirt" at him and not allowing him to respond, then "running out of" the hearing room "like a little girl" when it was over.
"This is all political theater," Homan said. "These people don't want the American people to hear the truth."
Democrats have thwarted the Trump administration and congressional efforts to fix loopholes in immigration law and court rulings that are serving as magnets for third-world poor to break into the United States. And while the White House has struck an agreement with Mexico to help interdict migrant convoys and perform better internal enforcement of its immigration laws, to some effect, U.S. border officials continue to deal with large numbers of migrants.
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The term racist is becoming more and more meaningless the more it's used so freely by the 'Rats to describe nearly everybody and every situation. Like whitener in your coffee? RACIST! Prefer vanilla ice cream over chocolate? RACIST! Like Castile soap instead of cocoa butter? RACIST! Let's see, there must be some way to interpret jaywalking as racist….
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text:
package org.wso2.carbon.sample.videoframes;

import java.io.File;

/**
 * The Class KeyStoreUtil.
 */
public class KeyStoreUtil {

	/** The file path to stor. */
	static File filePath = new File("src/main/resources/store");

	/**
	 * Sets the trust store params.
	 */
	public static void setTrustStoreParams() {
		String trustStore = filePath.getAbsolutePath();
		System.setProperty("javax.net.ssl.trustStore", trustStore
				+ "/client-truststore.jks");
		System.setProperty("javax.net.ssl.trustStorePassword", "wso2carbon");

	}

	/**
	 * Sets the key store params.
	 */
	public static void setKeyStoreParams() {
		String keyStore = filePath.getAbsolutePath();
		System.setProperty("Security.KeyStore.Location", keyStore
				+ "/wso2carbon.jks");
		System.setProperty("Security.KeyStore.Password", "wso2carbon");

	}
}

redpajama_set_name: RedPajamaGithub