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Comparing the use of aggregate data and various methods of integrating individual patient data to network meta-analysis and its application to first-line ART
BMC Medical Research Methodology volume 21, Article number: 60 (2021)
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The 2018 World Health Organization HIV guidelines were based on the results of a network meta-analysis (NMA) of published trials. This study employed individual patient-level data (IPD) and aggregate data (AgD) and meta-regression methods to assess the evidence supporting the WHO recommendations and whether they needed any refinements.
Access to IPD from three trials was granted through ClinicalStudyDataRequest.com (CSDR). Seven modelling approaches were applied and compared: 1) Unadjusted AgD network meta-analysis (NMA) – the original analysis; 2) AgD-NMA with meta-regression; 3) Two-stage IPD-AgD NMA; 4) Unadjusted one-stage IPD-AgD NMA; 5) One-stage IPD-AgD NMA with meta-regression (one-stage approach); 6) Two-stage IPD-AgD NMA with empirical-priors (empirical-priors approach); 7) Hierarchical meta-regression IPD-AgD NMA (HMR approach). The first two were the models used previously. Models were compared with respect to effect estimates, changes in the effect estimates, coefficient estimates, DIC and model fit, rankings and between-study heterogeneity.
IPD were available for 2160 patients, representing 6.5% of the evidence base and 3 of 24 edges. The aspect of the model affected by the choice of modeling appeared to differ across outcomes. HMR consistently generated larger intervals, often with credible intervals (CrI) containing the null value. Discontinuations due to adverse events and viral suppression at 96 weeks were the only two outcomes for which the unadjusted AgD NMA would not be selected. For the first, the selected model shifted the principal comparison of interest from an odds ratio of 0.28 (95% CrI: 10.17, 0.44) to 0.37 (95% CrI: 0.23, 0.58). Throughout all outcomes, the regression estimates differed substantially between AgD and IPD methods, with the latter being more often larger in magnitude and statistically significant.
Overall, the use of IPD often impacted the coefficient estimates, but not sufficiently as to necessitate altering the final recommendations of the 2018 WHO Guidelines. Future work should examine the features of a network where adjustments will have an impact, such as how much IPD is required in a given size of network.
With an ever-growing number of scientific publications, the need for meta-analysis to help make sense of the evidence continues to escalate [1]. Meta-analyses require that the included studies be sufficiently similar; otherwise resulting estimates may be biased due to imbalances between studies in the distribution of trial or patient characteristics that affect the relative effectiveness of the interventions being compared, named effect-modifiers [2]. Meta-regression has long been used to overcome such biases, as well as improve precision [3].
Meta-analyses typically consist of combining aggregate data (AgD) results from publications. As such, meta-regression most commonly consists of conducting linear regression of the study results as a function of an effect modifier, both in the aggregate. Two potential limitations to this form of meta-regression are: a limited number of data points to reliably estimate trends and risk of ecological fallacy (when trends at the trial-level do not match trends at the individual-level) [4]. A less common form of meta-regression involves using individual patient data (IPD), with or without AgD [5]. The use of IPD is less common, primarily due to the additional complications in obtaining such data [6]. Nonetheless, IPD meta-analysis can help overcome the two aforementioned limitations of AgD meta-regression [7]. Conducting meta-regression at patient-level values provide more data points, which also lends itself better to simultaneously adjusting for multiple variables [8].
Network meta-analysis (NMA) is an expansion of traditional meta-analysis that allows for the simultaneous analysis of multiple comparisons within a connected network of evidence [9]. Meta-regression is also an important technique to improve validity and precision of estimates in NMA [2, 10]. Given that NMA lends itself to larger evidence bases, the most common manner in which IPD is used in NMA is in analyses that include both IPD and AgD [11]. There are various ways by which to use IPD and AgD to conduct meta-regression, including two-stage approaches (whereby adjusted AgD are created using the IPD) [6], and one-stage approaches that integrate IPD and AgD together using hierarchical models [12,13,14].
In 2005, Simmonds et al. reported that 28/44 (63%) published IPD meta-analyses used the two-stage approach to IPD-AgD NMA. In a more recent 2015 review, the same researchers report roughly even use of one- and two-stage approaches, though outside of survival outcomes, the use of one-stage IPD-AgD NMA has become more popular [6]. There have also been further developments of ones-stage methods with Jackson et al. developing an expanded hierarchical method that may improve IPD-AgD meta-analysis by further reducing the risk of ecological fallacy [15, 16]. But there have not been many studies that have examined how the different types of meta-regression compare in their ability to improve analyses and conclusions. We sought to use a case study to examine if and which type (AgD or IPD) of meta-regression make such improvements.
The case study we used was a systematic literature review (SLR) and NMA that helped inform the 2016 World Health Organization (WHO) HIV clinical guidelines. The 2016 SLR found evidence of improved efficacy and tolerability of dolutegravir (DTG) relative to standard-dose efavirenz (EFV), the preferred first-line anchor treatment [17]. Following its completion, we sought IPD, independent of updating guidelines, for the comparison of AgD and IPD meta-regression methods and to see if more precise estimates might lead to stronger conclusions. In the 2016 analyses, DTG was nominally better than other treatments in its class, integrase inhibitors; however, these differences were seldomly statistically significant. In the same year, IAS-USA released its own clinical guidelines that suggested that all INSTIs were equivalent [18, 19]. We sought to further investigate this point.
The primary objective of this study, which was part of a doctoral thesis [20], was to compare the impact of using different established AgD- and IPD-based methods for meta-regression adjustments. A secondary objective was also to examine the change in outputs in the evidence synthesis of antiretroviral therapy (ART) among first-line HIV patients when including IPD – with a particular focus on the relative efficacy, safety and tolerability of DTG relative to other anchor treatments.
Systematic literature review
Study eligibility aligned with the review for the WHO Guideline update [21]. Briefly, eligible studies were randomized controlled trials (RCTs) comparing first-line ART regimens among adults and adolescents living with HIV. Eligible treatments were DTG, standard-dose EFV (low-dose) 400 mg efavirenz (EFV400), raltegravir (RAL), cobicistat-boosted elvitegravir (EVG/c), bictegravir (BIC), doravirine (DOR), rilpivirine (RPV), nevirapine (NVP), and ritonavir-boosted darunavir (DRV/r), atazanavir (ATV/r), and lopinavir (LPV/r); each in combination with a two nucleoside reverse transcriptase inhibitors (NRTI) backbone. The full PICOS (population, intervention, comparator, outcomes, study design) criteria are provided in the Additional file 1: Web-Appendix.
A comprehensive systematic search of the literature was conducted on 12 February 2018 using the following databases: MEDLINE, EMBASE, and CENTRAL (see Additional file 1: Web Appendix for search strategy). Further manual searches of the 2016–2018 Conference on Retroviruses and Opportunistic Infections (CROI), the 2016 AIDS and Glasgow HIV conferences, and the 2017 International AIDS Society (IAS) conference were conducted. Additional studies were identified through a review of clinical trial registries and the reference lists of identified publications. Two investigators, working independently, scanned all titles and abstracts identified in the literature search and reviewed subsequent full-texts. A third investigator provided arbitration as needed for discrepancies. The same approach was used for data extraction.
On 15 August 2016, IPD from three RCTs available through ClinicalStudyDataRequest.com (CSDR) were formally requested. These were FLAMINGO (DRV/r + 2 NRTIs vs DTG + 2 NRTIs) [22, 23], SINGLE (DTG + ABC + XTC vs EFV + TDF + XTC) [24,25,26,27], and SPRING-2 (DTG + 2 NRTIs vs RAL + 2 NRTIs) [28, 29]. Access to the data was granted on 06 June 2017. In hindsight, there was one more eligible trial that was available at the time through this service, namely the phase 2 SPRING-1 [30, 31]; however, it was still included in the analysis through AgD.
The validity of individual RCTs was assessed using the Risk of Bias instrument, endorsed by the Cochrane Collaboration [32]. This instrument is used to evaluate 7 key domains: sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias.
Reporting is in accordance with the preferred reporting items for systematic review and meta-analysis of individual participant data (PRISMA-IPD) guidelines [33].
Preparation of the individual patient data
IPD were provided in a series of lengthwise tables following the Clinical Data Interchange Standards Consortium (CDISC) standards. Using these tables, an amalgamated IPD set combining all three studies was prepared. The patients were restricted to the full analysis sets, as in each of the respective trials [22, 29, 34]. The following outcomes were obtained: Viral suppression and change from baseline in CD4 cell counts at 24, 48 and 96 weeks; discontinuations, discontinuations due to adverse events, serious adverse events. There were no missing values except for CD4, for which analyses were only conducted on the observed data. Data were further verified to ensure that published results for each trial could be obtained from the IPD.
Statistical models
Only select outcomes were used for the purpose of comparing the various statistical models of interest for conducting meta-regression adjustments with IPD and AgD. Assessing the impact on the HIV related results involved applying the preferred adjustment method to the remaining outcomes. The statistical models are presented below. Only the more complex random-effects models are presented, but both fixed- and random-effects were considered throughout.
AgD NMA
This served as the "baseline" results from which to draw comparisons. The model is as follows:
In this equation, θjk reflects the 'underlying' outcome for treatment k in study j that has been link-function-transformed to a normally distributed scale (e.g., logit link for dichotomous outcomes). δjbk is the trial-specific treatment effect of treatment k relative to treatment b. These trial-specific effects are drawn from a random-effects distribution: δjbk~N(dbk, σ2). The pooled effects, dbk, are identified by expressing them in terms of the reference treatment A. The heterogeneity σ2 is assumed constant for all treatment comparisons.
AgD NMA with meta-regression
Traditional meta-regression for NMA as described in the NICE Technical Support Document 3 [2], and the statistical analysis plan (SAP) [35].
Two-stage IPD-AgD NMA
For these analyses, aggregate values for the DTG trials were calculated using the IPD. Specifically, mixed linear regression among the IPD was used to model each outcome adjusted for candidate covariates and provide predicted estimates of the aggregate value within the target population. The adjusted values were then simply applied to the above methods.
One-stage IPD-AgD NMA with and without adjustments
IPD and AgD were combined, along with meta-regression, in a single model. This has the advantage of being a single model using all data. The model is shown in eq. (2), where θijk is the link-function-transformed parameter from the likelihood function of interest for the ith individual, in the jth trial, treated with treatment k. Similarly, ηjk is the link-function-transformed parameter from the likelihood function for the AgD. μjb and λjb are the study-effects for the IPD and AgD, respectively. When including meta-regression adjustment, for the IPD β0j is a study-specific effect of the subject-level covariate xij. β1Ak − β1Ab reflects the interaction effects of covariate xij for treatment k relative to control treatment b. k-1 different regression coefficient β1Ak will be estimated by the model. Parameters of primary interest from analyses are the pooled estimates of dAk, the estimates for the heterogeneity, and treatment-by-covariate interaction effects β1Ak.
Two-stage IPD-AgD NMA with empirical-priors
These models were the same as described in (2), except that the regression coefficients were provided with an empirical prior that was informed by the IPD. Rather than start with the non-informative prior for β1Ak, the IPD were first used to estimate meta-regression coefficients using mixed-effects linear regression. The estimates and standard errors of the meta-regression were used to construct an empirical prior: \( {\beta}_{1 Ak}\sim Normal\left(\hat{\beta},{prec}_{\hat{\beta}}\right) \). The idea here is to ensure that the IPD principally inform the meta-regression (potentially avoiding some ecological fallacy bias).
One-stage IPD-AgD NMA with hierarchical meta-regression
The final model that was considered was an expansion of one-stage IPD-AgD NMA that applies the hierarchical meta-regression adjustments first described by Jackson et al. and developed for NMA by Jansen et al. [15, 16] Unfortunately, these methods have only been developed for binomial outcomes. The model is shown in (3). It shares the same notations as (2).
The IPD part of this model is the same as that of the one-stage IPD-AgD NMA with adjustments, with the exception that β0 is not study specific but fixed across studies because it is now also used in the AgD part of the model (which reflects different studies). For the AgD part of the model, the number of events r in study j for treatment k is assumed to be binomially distributed with probability qjk and sample size njk. qjk can be considered as the average probability of the response of interest for an individual in study j treated with intervention k.
The covariate adjustment values β1Ak are distinct from those used in previous equations in that they are patient-level effects rather than trial-level effects. Even in the other IPD models, the effects are trial-level because they are estimated by both IPD and AgD. In (3) the values \( {q}_{jk}^0 \) and \( {q}_{jk}^1 \) are latent probabilities, therefore it is not possible to point identify β0 and β1Ak from AgD only. As such, these are solely estimated through IPD, which removes the possibility of the ecological fallacy bias entirely.
Statistical analyses
The following outcomes were used for the comparison of meta-regression methods: viral suppression and change from baseline in CD4 cell counts at 48 weeks (+/− 4 weeks), discontinuations, and discontinuations due to adverse events. We selected these because DTG and EFV400 are viewed to have as good or better efficacy and improved tolerability relative to EFV [36]. The target population was set to be the average population amongst EFV patients, the recommended preferred first-line regimen at the time. The following baseline variables were considered for covariate adjustments: CD4 cell counts, viral RNA (log-transformed), and proportion of males.
The three trials for which IPD were available tended to include healthier patients (higher baseline CD4 and lower baseline HIV RNA) and more males than the average EFV trial. In addition to being imbalanced, these factors were both plausible effect-modifiers and well-reported. Analyses consisted of comparing the modeling approaches described in the previous section. Identity link functions with Normal likelihoods were used for continuous outcomes. For dichotomous outcomes, logit link functions were use.
To assess the different models, the following measures were compared:
Treatment-effect estimates and posterior distributions of key comparisons.
Coefficient estimates and posterior distributions
Deviance information criterion (DIC) value comparisons across models, as well as pD and deviance
Between-study heterogeneity (between-study variance of the modelled outcome, e.g., log odds ratio [OR]; as calculated in the random-effects model)
The proportion of points falling outside the lines c = 3 and c = 4 within leverage plots (the curves are of the form x2 + y = c). Points outside of the lines with c = 3 can generally be identified as contributing to the model's poor fit (see TSD2) [37].
Change in SUCRA (surface under the cumulative ranking curve) scores
The posterior distributions for treatment-effect estimates are the output that are subsequently used to draw inference and for decision-making in Bayesian modeling. Therefore, this was a primary measure of modeling impact. There were no specific hypotheses regarding how these would be affected beforehand. For comparisons in treatment-effect, the absolute effect was used because it is the most interpretable. For example, a difference of 5% in the proportion of viral suppression is more interpretable than a difference of 1.5 in the logarithm of the odds ratio. For the dichotomous variables, a difference of 1% was chosen as the threshold of minimal clinically important difference. For a change in CD4, a difference of 10 cells/mm3 was chosen to align with the values that were used in the WHO reviews. The SAP for this study was publicly available prior to conducting the analyses and provides further details regarding methods [35].
The parameters of the different models were estimated using a Markov Chain Monte Carlo method implemented in the JAGS software package. The first series of 30,000 iterations from the OpenBUGS sampler were discarded as 'burn-in', and the inferences were based on additional 50,000 iterations using two chains. For all analyses, model convergence was assessed through trace plots, density plots and Gelman-Rubin-Brooks (shrink factor) plots [38]. All analyses were performed using R version 3.4.4 (http://www.r-project.org/) and JAGS version 4.3. Code used to conduct the analyses is presented in the Additional file 1: Web Appendix.
Evidence base
Study and patient selection are presented in the PRISMA-IPD [33] flow diagram in Fig. 1. The search was conducted in three phases: the first search of AgD was conducted in May 2015 (the original SLR), a search for IPD was conducted on 15 August 2016, and then an updated search of AgD was conducted on 12 February 2018. The IPD search in 2016 involved both YODA and CDSR; however, data were only obtained through CSDR. These included 2160 patients from FLAMINGO (DRV/r vs. DTG) [22, 23], SINGLE (DTG vs EFV) [24,25,26,27], and SPRING-2 (DTG vs RAL) [28, 29]. As shown in Fig. 1, the 2160 patients for which individual patient-level data were available represent 6.5% of the total evidence base (2160/33,148), and as shown in Fig. 2, the three trials cover a total of 3 of 24 edges (12.5%; shown in red) with trials providing head-to-head evidence.
Overall study quality was generally high (i.e., low risk of bias). Exceptions were restricted to open-label trials having a high risk of bias due to blinding and some of the more recent trials that were only reported upon in posters having insufficient information to determine with certainty that the risk of bias was either low or high (Additional file 1: Web Appendix).
The patient characteristics have been described previously [21]. As shown in Figure 1–4 of the Additional file 1: Web Appendix, in addition to being the variables that were best reported in the evidence base, the covariates selected for adjustments in this study had a high degree of variability. This was especially apparent in the baseline CD4. For full posterity, the reported results by study are provided in Tables 4–5 of the Additional file 1: Web Appendix.
Comparing meta-regression adjustments
Overall, the use of IPD appeared to have a negligible impact on the results. In each outcome, the use of IPD impacted an aspect of the results – say DIC, rankings or covariate estimates – but the aspect affected changed from one outcome to the next and tended to not be meaningful. The full set of results are shown for viral load at 48 weeks. For the remaining primary outcomes, tables and figures are presented in the Additional file 1: Web Appendix and only key highlights are focused on here.
Table 1 presents the model fit for the various models of interest for viral suppression at 48 weeks. The lowest DIC was for the unadjusted one-stage IPD-AgD NMA; however, the difference between it and the base model was not meaningful (requires a difference ≥ 3, as per SAP). The fit using the one-stage IPD-AgD NMA were considerably better than those using informative priors based on external analyses (two-stage empirical-priors approach). The use of IPD appeared to have minimal impact on the heterogeneity parameter estimate for this outcome (as calculated by the random-effects model). The proportion of observations above the third and fourth parabola in the leverage vs deviance plot tended to be stable. Nonetheless, the trend was towards having more outliers among the two-stage AgD NMA.
Rankings remained generally unchanged by the model choice. Change in rankings tended to happen in the models with the highest DICs and hence those were not at risk of being favoured. Changes in the top three rankings tended to be limited to a re-ordering of the same treatments, with DTG usually remaining on top (Additional file 1: Web Appendix).
Table 2 presents the estimated effects for the comparisons of primary interest (DTG, EFV400 and EFV). Meta-regression adjustments based on IPD tended to lower the estimated efficacy of DTG, but almost never rendered it non-significant. The exception was the use of hierarchical meta-regression, which was limited to single variable adjustments. Importantly, these analyses included much wider credible intervals than other analyses and this was consistently observed throughout the outcomes. This aligns with results previously presented by Jansen [16]. The analyses also led to the largest shifts in estimates and these were in either direction depending on the variable of adjustment. While these methods are noted for increasing validity, we cannot conclude bias in the previous analyses on the basis of these results. Mean and maximum changes in the log-odds were large across all analyses. These changes are more easily interpretable through the change in proportions, where the maximum change was often close to 4%. The difference between 86 and 90% of patients being virally suppressed would have important implications.
The estimated coefficients across the analyses are presented in Table 3. When comparing the meta-regression coefficients, the coefficient for CD4 was statistically significant in each of the IPD analyses that included it as a covariate. Moreover, its estimated effect size was consistent across the model using IPD. The coefficient estimates were notably different across AgD and IPD models, with HIV RNA leading the way.
For a change in baseline CD4 at 48 weeks, no models led to a meaningfully lower DIC than the unadjusted AgD NMA; however, contrary to viral suppression, here it was the two-stage models that appeared to have the best fit (DIC ranging from 182.02–184.23, relative to183.63 for the base model) among the IPD adjusted models (DIC up to 191.41 for the rest). Moreover, the two-stage analyses also reduced the number of points outside the fourth parabola in the leverage plots (0 vs. 1–3), suggesting an overall better fit to the data. The rankings were the measure most affected by choice of model for CD4. DTG was ranked first in the base case and in the IPD-AgD NMA, but EFV400 was ranked first when using AgD meta-regression and two-stage IPD-AgD NMA. DTG remained the favoured treatment in the one-stage and two-stage empirical-priors. With respect to the research question at hand, using a two-stage approach would impact how data were interpreted, given the change in rankings, particularly with DTG becoming a mid-ranked treatment and EFV400 becoming the number one ranked treatment.
Finally, with respect to CD4 most regression coefficients were not statistically significant, but similarly to the viral suppression analysis, the estimated coefficients using IPD were substantially different than those obtained through AgD meta-regression. For example, the effect of baseline HIV RNA went from 2.5 (95% CrI: − 21.2, 26.7) to 45.5 (95% CrI: 31.3, 59.9). In other words, the AgD meta-regression estimated that on average a trial initiating at a baseline HIV RNA that was one log unit higher led to a relative change in CD4 that was 2.5 cells/ml higher, whereas the one-stage IPD-AgD NMA estimated an average increase that was 45.5 cells/ml higher (keep in mind that trials did not differ by a full log unit of baseline HIV RNA).
For discontinuations, none of the models were meaningfully different from the base AgD NMA with respect to DIC. Change in estimates tended to be minimal across models. Interestingly, the exception to this was the HMR IPD-AgD NMA with adjustments for the proportion of males, which was also the model with the lowest DIC. In this model, both DTG (OR: 0.36; 95% CrI: 0.22–0.57) and EFV400 (OR: 0.61; 95% CrI: 0.30–1.23) were considerably more tolerable relative to EFV than in the unadjusted model, with an OR of 0.52 and 0.91, respectively.
Out of all the primary outcomes, only discontinuations due to adverse events had a model other than the unadjusted AgD NMA selected through a meaningfully lower DIC. In this case, it was the two-stage empirical priors approach with adjustments for the proportion of males that was selected with a DIC of 202.79 vs. 205.79. The one-stage analyses and two-stage empirical-priors analyses also led to a lower estimate of the between-study heterogeneity, suggesting that the adjustments helped account for between-study differences as well. The selected model shifted the principal comparison of interest from an OR of 0.28 (95% CrI: 0.17–0.44) to 0.37 (95% CrI: 0.23–0.58), but this would have little impact on decision making. With respect to absolute effects, most model adjustments led to minimal differences. This aligns well with the fact that none of the covariates were found to be statistically significant. The rankings were stable across models; however, with the selected model, DTG changed from being ranked 1st to being ranked 2nd.
Comparative efficacy and safety
Largely, results of the analyses for the secondary outcomes led to similar impacts to those observed in the selected four outcomes above. Only in the case of viral suppression at 96 weeks, the model adjusted for baseline HIV RNA was selected (instead of the unadjusted model). As shown in Table 4, the DIC for the selected model more than 12 units smaller than the AgD NMA. The table also shows that there are other adjustments that lead to similar DICs, but in this case, we've selected the smallest DIC. There was no meaningful impact with respect to rankings across outcomes.
The impact of adjustments with IPD on the actual estimates was noticeable, particularly in the case of viral suppression and change in CD4 cell counts at 96 weeks. In the case of viral suppression, the relative efficacy of DTG was reduced relative to both EFV and EFV400. In the selected model, the OR decreased from 1.94 (95% CrI: 1.52, 2.48) to 1.58 (95% CrI: 1.23, 2.03) relative to EFV, with a similar change relative to EFV400. While none of the effects changed with respect to statistical significance, the average change in modeled proportions was rather large at a mean shift of 4.1% in the selected model.
This study examined the change in outputs in the evidence synthesis of ART among first-line HIV patients when including IPD and compared the extent of this impact using different established IPD-based methods for meta-regression adjustments utilizing a mixture of IPD and AgD. The four methods of adjusting for covariate imbalances using IPD that were compared are: a two-stage approach, a two-stage approach with empirical priors, a one-stage approach, and hierarchical meta-regression. In this case study, none of the four methods stood out as a clearly superior approach solely on the basis of the numerical results. Nonetheless, this study does provide insights into these methods of adjustment. First, while in most analyses, the four strategies were in general agreement, there were situations where the results differed notably between the two-stage approach and other approaches, and thus the choice of method matters. Second, the hierarchical meta-regression tended to lead to the most considerable changes in effect estimates, but did so at the steep cost of reduced precision. Third, there was a remarkable difference in the coefficient estimates obtained through IPD methods and those obtained through more traditional meta-regression using AgD only, suggesting that when adjustments are needed, IPD is more appropriate to use. This study also aimed to understand the potential impact of including individual patient data for the particular application of comparing the therapeutic landscape of anchor treatments in first-line ART for the treatment of HIV. To this end, it was reassuring to find that the conclusions reached through the evidence synthesis supplemented by the individual patient data did not lead to changes that would have impacted the WHO change in guidelines that took place in December 2018 and subsequently in 2020 [39, 40].
The possibility that the limited impact of IPD on study results are due in part to the relatively small number of patients in the network providing IPD was investigated through a separate simulation study [41]. The simulation study was borne from this work. The aim of the simulation was to investigate various network factors that could be associated with the degree of benefits from including IPD, rather than to compare the various methods of adjustments, as was the goal here. The simulation study did find that the benefits of IPD are greater in small and/or sparse networks and that having too few IPD leads to negligible benefits. Another possible reason for the lack of differences between methods is a lack of ecological fallacy – whereby trends in AgD are do not reflect the trends in IPD – which is when differences between IPD and AgD adjustments are most important. Nonetheless, it is important to note that while there were minimal differences in the results between the multiple modeling methods, these do not imply that there are no differences between the methods. Several differences are still distinguishable within this case study, as further explained below.
Despite the limited impact on the interpretation of the therapeutic landscape on the basis of IPD, there are a number of advantages to the use of IPD that were observed and that have been discussed previously [6]. First, IPD more easily allows for the simultaneous adjustment of multiple covariates because it has much higher degrees of freedom. Only edges with multiple trials and differences in covariate values along those edges allow for the estimation of the covariate of interest in an AgD setting. Second, the results of this study suggested that where traditional AgD meta-regression was feasible, it was underpowered, as demonstrated by the estimated coefficients. Under the assumption that the IPD estimates based on 2160 data points are more accurate than the meta-regression adjustments based on trends among a small number of aggregate data points, the large differences seen in estimates suggest an inaccuracy among the AgD meta-regression.
There is a clear trend towards improved access to IPD and its increased use [11, 42, 43]. The most popular IPD methods have the distinct advantage of being able to adjust for unanchored networks, but require strong assumptions (no unobserved prognostic factors and effect-modifiers) and are usually limited to indirect comparisons [8, 44]. As the use of IPD increases, we can expect increased use of IPD-AgD NMA, such as the methods compared in this study. In terms of meta-analyses and network meta-analyses, there has been a shift from the predominant use of a two-stage approach to a one-stage approach [6]. As Simmonds et al. explain in their review, this is likely due to a growing familiarity with methods, improvements in computing and the recognition that regression model offers the greatest flexibility for IPD analysis [6]. The two-stage analyses in this study included the use of regression in the first stage, which was not always used in published two-stage analyses [6]. To the best of our knowledge, no study has compared the results of one-stage and two-stage IPD-AgD NMA directly. In most analyses, there were no meaningful differences in the results using either approach. Nonetheless, there were instances where one-stage and two-stage adjustments went in opposite directions. This may be a result of having the regression adjustments for the IPD done independently for each trial in the two-stage approach, rather than collectively. In the absence of differences, the two-stage approach had the advantage of being computationally less intensive and being easier to code. Conversely, the one-stage approaches had the benefit of having more easily interpretable regression coefficients and having all the analytical steps combined. Given these advantages and the fact that choice appeared to matter for some analyses, the recommendation would be to not use the traditional two-stage approach.
The choice between one-stage IPD-AgD NMA and two-stage IPD-AgD NMA with empirical-priors is less straightforward, and is ultimately dependent on the evidence base at hand. The difference between these two approaches was much more subtle. The empirical-priors method does not appear to have been used previously. As described in the methods, the motivation for its use was to isolate the coefficient estimation to the IPD (i.e., reduce the influence of the AgD on the estimation of the regression adjustments). As such, the greater difference is seen in comparisons for which there is no IPD, so that this method becomes more important when there are numerous comparisons with AgD only. Inspection of the DTG vs. EFV estimates, for which there was an IPD trial, reveals that there was general agreement between the two modeling approaches (when keeping the same covariates). On the other hand, for the EFV400 vs. EFV comparisons, for which there were no IPD available, the difference was notable, with the empirical-priors approach leading to a larger shift in estimates. In situations where there is an abundant number of trials and treatment comparisons that have IPD, such as in the Donegan et al. example [45], the one-stage approach, which is already well adopted, would be recommended. For networks of evidence that have few treatment comparisons with IPD trials, the empirical-priors approach is likely to maximize the IPD.
Although hierarchical meta-regression has shown some promising results, it appears that more research is still needed for these methods. Simulation work has suggested that these methods reduce bias [16], which is usually favoured over precision; however, the loss of precision observed in our work was not negligible. Moreover, it was difficult to use these methods with multiple variables at a time and the methods for use on continuous outcomes have not yet been published. Once further advancements are conducted on this method, it will be worthwhile reviewing a comparison with traditional one-stage analyses again.
As discussed above, the implications for first-line ART regimens (i.e., our secondary objective) are minimal. The evidence continues to support the DTG as the more efficient and tolerable choice of treatment. In instances where models were selected, the differences between treatments tended to be less pronounced, albeit DTG continued to perform best with respect to viral suppression, change in CD4 and tolerability.
There are several limitations to this study. First and foremost, there were very few trials for which IPD were obtained, which is a problem commonly encountered by researchers. These represented a small fraction of the trials and patients and may explain why the impact on model estimates appeared to be somewhat muted (i.e., too few IPD may get washed out in a large network). The limitation of too few data was exacerbated by the missed opportunity to get IPD for the SPRING-1 trial. The oversight was identified too far along in the process and thus could not be corrected in time. Given that this was a small Phase 2 trial that would have added a small fraction of patients to an already small sample of IPD, the impact of including or excluding its IPD is very likely to be negligible. Moreover, the SPRING-1 trial was still included in the analyses. Second, use of a single case study, particularly one with few IPD relative to the size of the network, limits the generalizability of the comparisons between the different methods of adjustments to other settings. To this end, while some conclusions have been reached, further research will be needed. Third, it is unclear whether the multiple forms of meta-regression interfered with one another. To account for differences in backbone regimens, an arm-based meta-regression was used in addition to the more traditional trial/patient-based regression adjustments, and this may have been a nuisance to the modeling process. Third, the trials for which IPD were available were principally conducted in high-income countries, which may limit the ability to make adjustments needed in studies conducted in the LMICs. Nonetheless, there tended to be a wide range of values for the covariates of interest, so this is unlikely to have been an issue [22, 23, 25]. Fourth, specific to this evidence base, there were numerous other potential effect-modifiers that were too poorly reported to allow for meta-regression adjustments to be made. These principally included ethnicity and acquisition risk groups. Finally, due to low event counts and data unavailability, not all outcomes were available for re-analysis using IPD.
There are many ways in which IPD can be integrated with AgD for the purpose of NMA. Choosing the method by which to integrate these data will impact results. In most cases, the one-stage approach is recommended; however, in situations with fewer treatment comparisons that have IPD, the empirical-priors approach is a viable alternative. Further research is needed to understand whether having too few IPD can mitigate their beneficial impact. Finally, even with the revised analyses, DTG continues to demonstrate improved efficacy and tolerability over other anchor treatments.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request (applicable only to data extracted from published manuscripts). The individual patient data that support the findings of this study are available from GlaxoSmithKline but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of GlaxoSmithKline.
Adverse event
- AgD:
Aggregate data
- AgD-NMA:
Aggregate data network meta-analysis without adjustments
- AgD-NMA-MR:
Aggregate data network meta-analysis with meta-regression adjustments
Antiretroviral therapy
- ATV/r:
Ritonavir-boosted atazanavir
Clinical Data Interchange Standards Consortium
Conference on Retroviruses and Opportunistic Infections
Deviance information criterion
- DRV/r:
Ritonavir-boosted darunavir
Standard-dose efavirenz
400 mg efavirenz
- EVG/c:
Cobicistat-boosted elvitegravir
Genomics Evidence Neoplasia Information Exchange
Hierarchical meta-regression
International AIDS Society
Individual patient data
Network meta-analysis with meta-regression adjustments, using both individual patient data and aggregate data
- LPV/r:
Ritonavir-boosted lopinavir
Matched indirect comparisons
Markov Chain Monte Carlo
Mean squared error
National Institute for Health Care and Excellence
Network meta-analysis
Nucleoside reverse transcriptase inhibitors
Odds ratio
Population adjusted indirect comparisons
Preferred reporting items for systematic review and meta-analysis of individual participant data
Potential scale reduction factor
Randomized controlled trials
Serious adverse events
Statistical analysis plan
Systematic literature review
Supporting Open Access for Researchers
Surface under the cumulative ranking curve
Tenofovir disoproxil fumarate
Lamivudine or emtricitabine
Yale University Open Data Access
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Walmsley S, Berenguer J, Khuong-Josses MA, Kilby M, Lutz T, Podzamczer D et al. Dolutegravir Regimen Statistically Superior To Tenofovir/Emtricitabine/Efavirenz: 96-Wk Data. Topics in Antiviral Medicine. 2014; Conference 21st Conference on Retroviruses and Opportunistic Infections, CROI 2014 (21) United States. Conference Start: 20140303 Conference End: 6. Conference Publication: (568 pages). 22 (e-1) (pp 261–262).
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The authors would like to thank Hubert Wong, Michael John Milloy and Tom Trikalinos for their critical feedback, as well as GlaxoSmithKline and the ClinicalStudyDataRequest.com programme for providing access to the individual patient data that made these analyses possible.
This work was supported by a CIHR (Canadian Institutes of Health Research) Doctoral Research Award. The IPD were provided by GlaxoSmithKline through the ClinicalStudyDataRequest.com programme. Neither agency played any role in the development and execution of the SLR and the analyses.
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Cite this article
Kanters, S., Karim, M.E., Thorlund, K. et al. Comparing the use of aggregate data and various methods of integrating individual patient data to network meta-analysis and its application to first-line ART. BMC Med Res Methodol 21, 60 (2021). https://doi.org/10.1186/s12874-021-01254-5
DOI: https://doi.org/10.1186/s12874-021-01254-5
- Individual patient data
- Network meta-analyses
- One-stage NMA
- Two-stage NMA
- Ecological fallacy
- Guideline development


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Turnagain Pass Avalanche Forecast
Most terrain around the Eastern Turnagain Arm has LOW avalanche danger this morning. Below treeline, the danger will rise to MODERATE late in the day for human triggered wet loose avalanches as temperatures climb. Additionally, there are pockets of MODERATE danger on steep upper elevation slopes where it is possible to trigger a shallow stiff wind slab just below ridgelines.
For Monday, avalanche conditions look to be similar to today. Keep in mind, if warm wet weather moves in mid-week you can expect the avalanche danger to rise.
Today will be our final advisory for the season. Stay tuned for a springtime avalanche concern write up and a brief season recap on May 1st. Also, our annual report will be coming out in the next week or so – watch for that on our resources page.
But most importantly: A huge THANK YOU to all of our supporters, donators and observers for making the Chugach National Forest Avalanche Center a reality. We could not do it without you!!
The north winds have ravaged the upper elevations. We continue to hear of parties feeling collapsing and whoomphing on ridgelines and some able to trigger slabs 2-6″ thick. These slabs may be shallow but they are stiff and can be dangerous if triggered in 'no fall' zones (i.e., over cliffs). Since most of the higher terrain has significant wind affect, you are likely to find many areas with a breakable and annoying wind crust along with the scattered areas of wind slab. Unsupported slopes are the most concerning (see the second photo for an example of this). Our unusually cool spring has allowed the facets below these slabs to persist and wintertime cold snow issues to remain above treeline.
Photo is of Graham Predeger monitoring the breakable wind crust Saturday that covers most upper elevation slopes. This is near the top of the Burns glacier ~4,000ft.
Below treeline today, and on southerly aspects with little wind, you can expect the crusty surfaces to warm up late in the day. The cool temperatures and breeze may keep warming limited, however if you do come across a slope with more than 6 inches of mushy wet snow avoid it. If this is the case triggering a wet loose snow avalanche is quite possible and can entrain a lot of heavy snow and run far.
Below is a photo from Saturday. The wet avalanche activity is a few days old (from Tues/Wed) but the picture demonstrates what our mountains look like and the variable nature of the snow conditions.
The much anticipated "shed cycle" has not produced yet and maybe this will be one of those years we don't really see it. The cool northerly flow and clear nights has kept the pack from warming up. However, we do have a warmer system moving in this week so keep your eye out any avalanche activity associated with this.
Sunny skies prevailed once again yesterday. Winds were light from the northwest in the 5-10mph range. Temperatures climbed to the mid 20'sF on the ridgelines and low 40'sF at 1,000′.
Today should be another brilliant day in the backcountry with the only change being breezier northerly winds. The winds kicked up last night (averaging 10mph gusting 23mph on Sunburst and bit more at Seattle Ridge) and will be on a slow decrease today. Expect ridgetops to blow in the 10-15mph range with gusts to 30mph from the north. Temperatures will again climb into the 20'sF at the upper elevations and ~40F at 1,000′.
For Tuesday into Wednesday look for a change in the pattern. Models are showing a shift back to a moist southwest flow with the approach of a low pressure system in the north Pacific. Warmer temperatures, clouds and precipitation should return to the Eastern Turnagain Arm.
Helpful weather links:
CNFAIC weather page
MountainWeather.com's Alaska Page
This wraps up our final advisory for the season. We will be updating this page around May 1st with springtime avalanche concerns so check back mid-week. Thanks!
|Avalanche: Tincan
|Nick D'Alessio
|Avalanche: Tincan, Sunburst, Magnum, Cornbiscuit
|Heather Thamm
|Observation: Tincan – Bear Tracks
|CNFAIC Staff
|Observation: Seattle Ridge
|AS/ WW Forecaster
|Observation: Cornbiscuit
|Schauer/ Sturgess Forecaster
|Observation: Seward Hwy Turnagain Pass
|Joel Curtis
|Observation: Magnum
|Ayla, Kit Crosby, Barton
|Observation: Tincan
|John Sykes
|Avalanche: Taylor Pass/Pastoral
|Schauer/ Creighton Forecaster
|Avalanche: Tincan
|Andy Moderow
Status of riding areas across the Chugach NF is managed by the Glacier and Seward Ranger Districts, not avalanche center staff. Riding area information is posted as a public service to our users and updated based on snow depth and snow density to prevent resource damage at trailhead locations. Riding area questions contact: email@example.com
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|Glacier District
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This is a general backcountry avalanche advisory issued for Turnagain Arm with Turnagain Pass as the core advisory area. This advisory does not apply to highways, railroads or operating ski areas.

subset: commoncrawl


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The bond market is where participants can issue new debt or buy and sell debt securities to provide long-term funding for public and private expenditures. Now that you know how and where to buy bonds, you probably want to know about the actual bond market.
What is the Bond Market?
The bond market is a financial market where participants can issue new debt. Also referred to as the debt, credit or fixed-income market, it includes securities issued by the government and corporate debt securities. Its purpose is to provide long-term funding for both public and private expenditures.
The stock market often hogs the media attention, but the bond market is actually significantly bigger! It's also quite vital to the ongoing operation of both the public and private sector.
The majority of trading in the bond market happens over-the-counter and is composed of both the primary market and the secondary market. Debt securities are issued and sold by borrowers to lenders through the primary market. It's through the secondary market where investors buy and sell previously issued debt securities among themselves.
Bond Market News
There are many places you can receive bond market news. Here are your best resources:
General bond market tips
Investing in bonds isn't for everybody. While many experts agree that at least some of your portfolio should be made up of bonds, there are certain types of investors who fit the mold a little better.
You would be more likely to invest in bonds:
1. If you are a relatively conservative investor.
Bonds are considered to be a safer alternative to stocks in the short term. They are less volatile, meaning there will be less swings.
2. If you feel the stock market is too risky and you want to make sure all your eggs aren't in the same basket
Stocks tend to outperform bonds over time. Though in the short-term, bear markets could cause your stock investments to lose value. However, as the graph below indicates, Bonds have typically been more stable than any other asset.
3. If you cared more about generating income from your investments rather than appreciation.
Bonds pay a regular interest rate (income) but usually do not go up in value as much as stocks, ETFs or mutual funds do.
4. If you are a retiree
Investors in retirement have a shorter investment horizon. Therefore you will care more about income generation and safety.
Some of the key variables to look at when deciding whether to invest in bonds are: their maturity, redemption features, credit quality, interest rate, price, yield, and potential tax benefits. Together, these factors help determine the value of a bond investment and how well it matches your personal investment goals.
International bond market
International bonds are just debt investments that are issued in a country by a non-domestic entity, in their native country's currency. The main benefits of investing in international bonds are portfolio diversification, higher historical returns and currency benefits.
While they do offer diversification opportunities, foreign bonds can also carry considerable risk. Currency and default risks are the biggest concerns.
Due to multiple levels of risk, investing in global bonds is often best left to a portfolio manager. Most international bond issues are difficult to purchase directly from the sovereign government or offshore corporation that issues them. In some cases, actually, foreign governments won't even allow the purchase of government bonds by non-residents! So even if you feel comfortable…we'd still push for a portfolio manager.
Junk bond market
Junk bonds aren't really all that different from regular bonds. They, too, are a debt from a corporation or organization. Like regular bonds, a junk bond will have a principal (amount to be paid back), a maturity date (the date by which it will be paid back) and a coupon (interest rate). The different is the issuer's credit quality.
Their poor credit rating makes it difficult for them. Junk bonds pay high yield to bondholders because the borrowers don't really have other options. Junk bonds are typically rated 'BB' or lower.
Junk bonds can be broken down into two subcategories:
- Fallen Angels – A bond that was once investment grade but has since been reduced to junk-bond status because of the issuing company's poor credit quality.
- Rising Stars – A bond on its way to being investment quality, whose rating has been increased because of the issuing company's improving credit quality.
Despite their name, junk bonds can be valuable investments for informed investors. Just be sure to understand that with their potential high returns comes the potential for high risk!
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Lashtail Hatchling Quests
Share pet collecting news and advice.
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7 posts •Page 1 of 1
Does anyone know how to get the quest "An Old Friend" that allows one to get the "yourname 'Aka" Lashtail Hatchling pet? I completed the Stanglethorn quest chain through "Be Raptor" and its turn-in, but the quest giver did not offer me the Troll raid quest "An Old Friend". My guild is planning a run for the pet, but I do not want to do the raid without the final quest. My toon is a 90, so I know it is not a leveling problem. Any help is welcome!
- Maizing
- Posts:376
- Joined:October 15th, 2012
- Pet Score:5724
- BattleTag®:Maizing#1456
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Re: Lashtail Hatchling Quests
You get the last quest when you do the instance. It is the quest itself that awards the pet.
- Angelwings626
- Posts:217
- Joined:July 26th, 2013
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Re: Lashtail Hatchling Quests
^ what Maizing said =D. It's super cute. You just need to kill the guy with the raptor bone pet, (the one in the circle where someone gets sacrificed throughout the battle, but the spirits rez you). She'll pop up after the battle... =D
Re: Lashtail Hatchling Quests
Thank you! So, I think I understand..I will be able to pick up the quest when I actually enter the raid instance...I assume its available at the entry to the instance, like the quests in a regular dungeon? Or does the quest just appear on the pet after I kill the last guy?
Re: Lashtail Hatchling Quests
No. After you kill the boss, you will see your raptor chained up with a quest available. Complete it and yes yours.
Re: Lashtail Hatchling Quests
Thanks for all the help!
Re: Lashtail Hatchling Quests
I soloed this at 90 so it should be easy for you to get. GL!
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7 posts •Page 1 of 1


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The Dodge Charger, in its modern incarnation, is a rear-wheel power enormous vehicle constructed with the aid of using the DaimlerChrysler organisation for its North American Dodge brand. The Charger call is a historic one, borne with the aid of using many different Dodge Charger fashions withinside the past; they have got commonly been overall performance fashions.Introduced in February 2005 for the 2006 version year, this new Charger stocks the LX platform of the Chrysler three hundred and Dodge Magnum; in fact, the indoors of the Charger is nearly same to that of the Magnum. It changed the Dodge Intrepid as Dodge's enormous sedan. This Charger is a four-door sedan, disappointing a few lovers of the preceding -door Chargers. It is constructed at Brampton Assembly in Canada.The Charger SE and SXT are prepared with Chrysler's 3.5L V6 and sells at a beginning rate of $22,995 USD. The 3.5L V6 produces 250 hp (186 kW) and 250 ft·lbf (339 N·m) of torque. (observe that there may be additionally a 2.7L to be had for fleet income simplest, which produces one hundred ninety hp and one hundred ninety ft·lbf of torque.)The R/T model makes use of the 5.7L Hemi V8 and sells for $29,995 USD. This engine produces 340 hp (254 kW) and 390 ft·lbf (475 N·m) of torque.The SRT-eight version comes with the 6.1L Hemi V8 and has a base rate of $35,320 USD. The 6.1L Hemi produces 425 hp (317 kW) and 420 ft·lbf (569 N·m) of torque.
The 2006 Charger Daytona R/T debuted on the Chicago Auto Show. It functions a High Output 350 hp (261 kW) model of the 5.7 L Hemi in addition to an up to date suspension and tires. Visual additions encompass a unique the front fascia with a chin spoiler. In a unfashionable touch, the Daytona R/T functions black "Hemi" decals at the hood and rear fender and is simplest to be had in unfashionable colors: "Go ManGo!" steel orange (from the 1970 Charger) and Top Banana yellow (additionally a 1970-antique colour). It is priced at US$32,495 and eight,000 could be produced for three hundred and sixty five days simplest. "TorRed" become introduced as a brand new colour in January 2006.
An SRT-eight model of the Charger debuted on the 2005 New York International Auto Show. Powered with the aid of using a 425 hp (317 kW) model of the 6.1 L Hemi, it additionally functions upgraded Brembo brakes, and indoors and outdoors updates. The engine produces 420 ft·lbf (569 N·m) of torque. The 425 NET horsepower of the current 6.1L Hemi makes it even greater effective than the mythical Hemi engines of the muscle automobile era, the most important of which become rated at 425 GROSS horsepower. This makes the 6.1L Hemi engine the maximum effective V8 engine that Dodge/Chrysler has ever installed a manufacturing vehicle.


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text: Pleurtus eryngii, also known as king trumpet, french horn, and king oyster mushroom is an edible mushroom native to the Mediterranean regions of Europe, the Middle East, and North Africa. It is the largest of the Pleurotus genus. Unlike other species of oyster mushrooms, which are wood-decay primarily, the King Oyster mushroom are also weak parasites on the root systems of plants. It has a long shelf life, does not smell when raw, and has a umami flavor and meaty texture when cooked. King Oysters may have agents that stimulate the immune system and could function as a cholesterol-lowering dietary device. Spores are 7-9.5 µm x 3.5-4.5 µm in size


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Since it almost went broke in 2010, Greece has suffered horrific job losses, soaring long-term unemployment, across-the-board income cuts and over-taxation, despite a constant deterioration in state-provided health, education and welfare services.
The country is now dotted with the hulks of formerly flourishing factories that for decades churned out wealth for their owners and provided a sure if modest livelihood for multitudes of workers. While many predate the country's financial crisis, the past five years have accelerated the pace of de-industrialization.
Beyond the derelict factories with their cracked concrete platforms and smashed windows, there's the old Athens airport complex, abandoned since 2001, and former farmland in the southern Peloponnese region.
Some of the plants are guarded by former staff, others padlocked or open to anyone prepared to dirty a pair of trousers. Inside are the relics of their former activity: Piles of wine bottles, stacks of crockery, idle machinery. Scattered among them are the imprints of the people who worked there — rotting boots and gloves, personnel files, dust-infused jackets left hanging on nails and never reclaimed.
Here's a gallery of photos by Associated Press staff photographer Petros Giannakouris showing some of Greece's abandoned places.


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Look at these cool ideas for the loved one on your list. Queen Street duvets or something else entirely depending on your personality. Maddie created several looks for you to be inspired. Enjoy your weekend. love, The Boomers!!
SO pretty. I just LOVE Queen Street. Simply gorgeous fabrics.
Great gift idea for sharing the Sis Boom Love!
Love the inspiration sketches! And the color combos are gorgeous. Can't wait to try some experimenting with the new Queen Street.
Now that would certainly give you sweet dreams – good job!
And you know who can help your Sis Boom bedroom dreams come true? Me!
"Got Quilt?"
Love all those cozy combos!! Also, love the dress on the girl hanging the wreath on your home page. Is that a dress that you have a pattern for? Its hard to tell! 🙂


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Jul 23, 2013
Fifth & Pacific close to selling Lucky Brand to Advent
Jul 23, 2013
Apparel company Fifth & Pacific Cos Inc is in late-stage talks to sell its denim business Lucky Brand to private equity firm Advent International, according to three sources familiar with the process.
Fifth & Pacific could not be reached for comment. Advent declined to comment.
The company, formerly known as Liz Claiborne Inc, hired investment banks Centerview Partners and Perella Weinberg earlier this year to sell its Lucky and Juicy Couture labels as it looks to focus on its fast-growing kate spade brand.
Jos. A. Bank Clothiers Inc also took a look at Lucky, the sources said.
The sources, who declined to comment because the matter is not public, cautioned that a deal for Lucky is not finalized yet and may still fall apart.
During the first quarter, Lucky's net sales were $117 million, up 16.5 percent from the same period in 2012. It generated adjusted earnings before interest, taxes, depreciation and amortization of $5 million during that period.
In January, the company said it expects Lucky to generate adjusted EBITDA of $50 million to $55 million in full-year 2013.
At the end of 2012, Lucky had 177 full-priced stores and 47 outlet stores.
© Thomson Reuters 2023 All rights reserved.


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Christmas Eve at Hafjell Hotel
The menu on Christmas Eve is traditional Norwegian Christmas food with a large Christmas buffet for hotel guests and everyone else who wants to experience Christmas Eve at Hafjell Hotell. On Christmas Eve, guests at the hotel will enjoy the Christmas Dinner. Many of the guests are also from other accommodation establishments and cabins in Hafjell.
Christmas Eve program
09.00 - 14.00 Hafjell ski resort is open
16.00 Deadline for delivery of Christmas packages at the reception for later distribution of Santa Claus. Up to 1 package per guest.
17.00 Traditional Norwegian Christmas dinner. The starter is served at the table by the waitress, the hot food and the dessert are served by the chef in the food market.
19.00 Santa Claus arrives at the hotel. Coffee, hot juice and cakes in the Fireplace Room.
19.00 - 21.00 Playland is open for hotel guests. Note: Unmanned - an adult must be present
Welcome to Hafjell Hotell on Christmas Eve!
Christmas buffet on Christmas Eve is included in the price if you order our pension offer over Christmas.


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Java Reflection API provides support for querying information about a class at run-time. This information includes the list of public as well as private members (methods) available for the class, the various public operations it supports etc. This section will guide you in making use of the Reflection API. Suppose we have the following test class containing two methods,
also read:
- Java Tutorials
- Java EE Tutorials
- Design Patterns Tutorials
- Java File IO Tutorials
package tips.reflection; public class TestClass { public int a = 10; private int b = 32; public String name = "TestClass"; public void method1(){ System.out.println("Method1 is called. a = " + a); } public void method3(){ System.out.println("Method3 is called. name = " + name); privateMethod(); } private void privateMethod(){ System.out.println("A private method "); } }
If we want to get the class information for
TestClass, then we have the following program. The following program dynamically loads the
TestClass by calling the
Class.forName("className"). It should be noted that while specifying the class name within
Class.forName(), the fully qualified name of the class (i.e package name + class name) should be specified. Then to retrieve all the defined methods in the class, a call is made to
Class.getDeclaredMethods() which returns all the methods as an array. Same happens while retrieving the fields.
The next block of code performs dynamic invocation of the method
method1. It first gets a reference to the method
method1 by calling
Class.getMethod("method1"). Then using the
Method.invoke() method, an invocation is performed on the
method1 method by passing the original object along with an array of arguments the method is going to accept. Since in our case, the method
method1 doesn't accept any arguments an empty Object array is passed to the
Method.invoke() method.
package tips.reflection; import java.lang.reflect.Field; import java.lang.reflect.Method; public class ReflectionTest { public static void main(String[] args) throws Exception { Class<?> classObject = Class.forName("tips.reflection.TestClass"); Method allMethods[] = classObject.getDeclaredMethods(); for(Method aMethod : allMethods){ System.out.println("method : " +aMethod.getName()); } Field allFields[] = classObject.getDeclaredFields(); for(Field aField : allFields){ System.out.println("field : " +aField.getName()); } Object testClass = classObject.newInstance(); Method aMethod1 = classObject.getMethod("method1", new Class[]{}); aMethod1.invoke(testClass, new Object[]{}); } }
The output of the above code is,
method : method1 method : method3 method : privateMethod field : a field : b field : name Method1 is called. a = 10
In this section, we saw a simple example of using Reflection API. This API can be further explored and be effectively utilized based on our needs.


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The Republicans really are in their own little world. Instead of trying to help the 99% they instead voted on a "God check" bill titled "H.Con.Res 13 — Reaffirming 'In God We Trust' as the official motto of the United States." The jobs are where…???
The resolution, which went through an expedited process requiring acquiescence of two-thirds of the House, passed 396 to 9, with all but one of the no votes coming from Democrats; two members voted "present." The Senate had passed a similar measure in 2006 when Republicans controlled that chamber.
Representative Eric Cantor of Virginia, the House majority leader, said earlier this year that he would try to prevent votes on measures that were not "substantive and meaningful." The House did not vote, for example, on an independent resolution, passed in the Senate this year, to honor the troops who carried out the mission that killed Osama bin Laden. His office did not respond to a request for comment on Tuesday.
Symbolism isn't reducing the increase in people getting food stamps or the unemployment rate.
The resolution is as meaningless as the hand checks we use to do in grade school.
Jerrold Nadler (D-N.Y.) said on the floor of the House:
"Today we are returning to irrelevant issues that do nothing to promote economic growth to put Americans back to work," Nadler said. "We've seen this before. In the 107th Congress, we passed a bill to reaffirm the phrase 'one nation under God' in the Pledge of Allegiance and reaffirm the national motto. We went so far as to reenact into law word for word the existing law making 'In God We Trust' the national motto, just to be sure. No one had threatened it. No one had said 'it's not the national motto.'
"This resolution today, which has no force of law, simply restates the national motto once again," Nadler noted. "Why have my Republican friends returned to an irrelevant agenda? Why are we debating non-binding resolutions about the national motto? The American people are demanding action on the president's jobs legislation. And yet here we are back to irrelevant issue debates, the kind of thing people do when they have run out of ideas."
Yep that and the Republicans don't want to do anything to really fix the economy.


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According to UFC President Dana White, the promotion is getting back to business soon, there will be plenty of work to go around, and yes, "Fight Island" is a real thing.
During an invite-only teleconference convened to address the promotion's response to the COVID-19 pandemic, White tried to reassure contractees that the UFC is coming back in a big way.
White said the promotion will reboot live events starting on May 9 and hold weekly events in the U.S. He added the company is working with state officials to have them at the promotion's APEX facility, but official locations for the May 9 pay-per-view card and subsequent cards remain TBA.
Additionally, White promised that every UFC fighter who wants to, will be able to fight three times this year, and he said "Fight Island" will be up and running by late May or early June. The promotion was forced to postpone four events, including the banner UFC 249 card, amid shutdowns caused by the pandemic.
Apart from a timeline for the tropical combat itinerary, White's comments were characterized as a rehash of previous interviews he's given about the promotion's plans, according to several fighters who attended the meeting and spoke on the condition of anonymity because they feared reprisals from the promotion. Managers and other "third parties" were not allowed to attend the meeting, per an invite obtained by MMA Fighting.
One fighter called the meeting "kinda pointless" and took White to task for not disclosing the event's locations. The teleconference was set up so that fighters could not see who else was attending the call or who was asking questions during a Q&A portion of the call.
At one point, White attacked the media for what he saw as inaccurate reporting about plans for the ill-fated UFC 249 and scoffed, "The media are not your friends." Several times, he asked for serious questions from the fighters and reassured them that if they felt uncomfortable about the coronavirus, they don't have to compete.
Several fighters said they hadn't checked their emails and didn't know about the meeting until contacted by MMA Fighting. They said they would attend the next session, scheduled for Monday, April 20.
Here are a few points relayed by attendees, several of which were first reported by MMA Junkie:
- Fighters who had fights postponed are prioritized for rebooking.
- White expressed a dislike for catchweight bouts and said fighters should probably wait until they can make weight before they compete again.
- Matchmakers will contact fighters to re-book fights and will help as much as they can with medical exams, and the promotion will purchase flight tickets for as many corners as possible for "Fight Island."
- The location of "Fight Island" on international waters means people will be able to fight without visas.
- The UFC is currently negotiating to open the APEX and the UFC Performance Institute
- The UFC is working with the Nevada government to promote in Vegas starting in May, but they haven't finalized anything yet. The upcoming fight cards will likely be in the U.S.
- International Fight Week is unlikely to happen.
- The Trifecta meal service for fighters will be back soon.


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Posted - 2018-10-23← Back to News and Media
TORONTO--(BUSINESS WIRE)--BaneCare Management LLC, a Massachusetts-based senior care provider operating 12 facilities, leveraged PointClickCare's electronic health record (EHR) platform and insights from patient satisfaction surveys to gather and analyze actionable data to improve patient care.
BaneCare quantifies its level of patient satisfaction based on the rating it receives from the CoreQ patient experience survey. After noticing a variance in their results, BaneCare created its own survey that collected data on patients' experiences during the admission process. Survey questions focused on three critical areas:
Click Here to view the full article.


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Ice Cube Names Chuck D His Favorite Rapper & Bomb Squad His Favorite Producers (Audio)
February 21 UPDATE: The video interview of Ice Cube from The Combat Jack Show has been added below, along with the existing audio stream.
Original Post:
Starting in 1990's "Endangered Species (Tales From The Darkside)," Ice Cube made some of his most notable collaborations with Chuck D and the producers of Public Enemy, The Bomb Squad. In a career that has included collaborative work with Tupac Shakur, The D.O.C., Snoop Dogg, Scarface, and Kool G Rap, Cube tells The Combat Jack Show about just what Public Enemy's Carlton "Chuck D" Ridenhour means to him.
At 31:00 into the interview, Combat Jack mentions to Cube that he's worked with two of Hip-Hop's most celebrated production acts in Dr. Dre and The Bomb Squad. "The Bomb Squad was…they're the standard. When it comes to sampling [in] that era, nobody could do it like The Bomb Squad. They was mad scientists. They were dudes who were more creative. Their beats hypnotized you." After leaving N.W.A. in 1990, Ice Cube and longtime collaborator Sir Jinx traveled to New York to work with Public Enemy and The Bomb Squad on his AmeriKKKa's Most Wanted solo debut. That team including brothers Hank and Keith Shocklee, Eric "Vietnam" Sadler, Chuck D, and G-Wiz.
Cube continues, "Sonically, [they are] on a whole 'nother level. These dudes were geniuses with sampling and putting music together in that era. I know I worked with Dre [chuckling], but The Bomb Squad is my favorite producers. 'Cause they were what [N.W.A.] was trying to emulate in a lot of ways with Straight Outta Compton [which has] a lot of them break-beats [including 'Fuck Tha Police']. The start of [that record] is 'Bring The Noise' [mimics the beat]. We're using these same break-beats to create our stuff because we're so influenced by Public Enemy."
Ice Cube Announces 25th Anniversary Edition of Death Certificate With New Songs (Video)
"They were, to me, more politically-focused than N.W.A.," admits Cube. Straight Outta Compton released less than 40 days after P.E.'s sophomore LP, It Takes A Nation Of Millions To Hold Us Back, which included the aforementioned "Bring The Noise." "We got one or two [political songs]; they got 30, 40. [Chuckles] Our focus was just a little different than theirs. They had Knowledge Of Self; we were still mental zombies, as far as our place in the world. We was just thinking that the police was the biggest obstacle, until we got the letter from the F.B.I. Then, we started to really understand our place in the world, and me personally, started to understand what it is to be Black at that time. These dudes helped us get over the hump with that. I'm always [saluting Public Enemy]. Chuck is my favorite rapper of all time, because of message and content. [Those skills in Chuck D are] off the meters compared to any other rapper in the game. Salute to Chuck; he really kicked this off."
Ice Cube and Chuck D would work together again on Bootsy Collins' Tha Funk Capitol of The World.
Allen Iverson Will Play In Ice Cube's New BIG 3 Basketball League (Video)
At the close of the interview, Ice Cube lists his Top 5 of all-time as Chuck D, KRS-One, Rakim, Grandmaster Melle Mel [of Grandmaster Flash & The Furious 5], and LL Cool J. Cube maintains that list is not ranked.
Sir Jinx Speaks About Keeping The Production On Ice Cube's Death Certificate True To The Game
Cube's Fist Fight film opens this week. He is presently preparing for a 25th anniversary re-release of Death Certificate. It will reportedly contain three new songs.


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- Expired!
Jeff Pitchell, Texas Flood & The Fabulous Jeffettes
Jeff Pitchell is an internationally acclaimed dynamic singer, songwriter, guitarist, and actor. Jeff achieved national recognition when one of his CDs, Heavy Hitter (Pyramid Records/EMI) reached #7 on the Billboard Charts, selling more CDs than Delbert McClinton, Robert Cray, Etta James, Johnny Lee Hooker & Muddy Waters. Jeff has recorded with such greats as Rick Derringer, Dave Mason, James Cotton, Clarence Clemons, Phil Lesh, Gregg Allman and the Allman Brothers, J. Geil, etc. Jeff received international recognition when he toured Europe and then was asked to join the Commitments as a special guest. Jeff and Texas Flood have been honored to have been voted the Best Blues Act in New England in six state vote..Jeff has been further honored by being inducted into the Blues Hall of Fame..
Texas Flood consists of Mario Perett on sax (formerly with James Taylor and The Temptations), Lorne Entress on drums (drummer for Ronnie Earl), John O'Boyle on bass, Dan Fontanella B3 Organ. These seasoned musicians unite to bring a high energy mix of Rhythm and Blues, Rock Soul, Pop and funky Texas Blues.
The Jeffettes 2-piece vocal harmony group consists of Linda Ransom and Theresa Wright. They have performed for 25 years with various Gospel and jazz groups throughout the United States, Canada, Europe, and the Caribbean. Their soulful harmonies are truly amazing and their lead vocals are breathtaking.
Together, this accomplished group of musicians will entertain you with their hard driving brand of thunder and lightning blues, rock, funk, and soul music.
Wind: 4 MPH
Humidity: 100 %
Feels like: 62 °F


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Solar Photovoltaic Projects in the Mainstream Power Market (Hardback)Philip Wolfe (author)
Published: 22/10/2012
This is the first and probably the only book devoted to utility-scale solar power - perhaps the fastest-growing sector of the global energy market.
Philip Wolfe's book describes the development and operation of large-scale solar power stations, and will interest all those who want to understand how these multi-million dollar projects are designed, structured, financed, constructed and maintained. It contains case studies of the Waldpolenz Energy Park, Germany, Lopburi Solar Plant in Thailand and the Topaz Solar Farm in California. Also included are interviews from leading figures in the PV industry.
It shows the state of the world market and links to an online resource that continues to track the explosive growth of the sector.
The book is arranged in three sections:
A description of solar projects in context, and how they are undertaken. Chapters on developing and structuring projects; siting, consenting and connection issues; building and operating solar plants; design and technology basics; economies of solar photovoltaics.The second section reviews individual aspects of the project development and operational process in more detail. In particular it advises on strategies to manage technology, commercial, regulatory and implementation risks.These are supported by a comprehensive reference section, including case studies and overviews of key parameters applicable in different parts of the world.
Supported by figures and photographs, this book is for anyone wanting to master the commercial, professional, financial, engineering or political aspects of developing multi-mega-watt solar PV projects in a mainstream power market. It is a 'user manual' to accompany a sector which by 2015 had surpassed a value of $100 billion.
Publisher: Taylor & Francis Ltd
Number of pages: 240
Weight: 536 g
Dimensions: 234 x 156 x 15 mm
"... an excellent introduction to the solar photovoltaic project development and power markets sector... for those interested in learning how to develop a large- scale solar photovoltaic project and its related environmental impacts, Solar Photovoltaic Projects: In the Mainstream Power Market is the best book and most- easily assessable book available." - Gabriel Thoumi, CFA, Mongabay.com
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Benchill Community Centre
Benchill Community Centre offers a range of community and leisure activities and has strong links with further education providers.
There are the following facilities:
IT Suite
First floor IT Suite which is fully air conditioned and user friendly consisting of 14 computers with internet access and an on-site IT support tutor packages.
Community Room
The community room facilities are available on the ground floor of the new building and include a bar (un-stocked), DJ booth and soon to be erected cyber cafe. This is a multi-purpose room is presently being used for youth provision, meetings, dance groups, parenting courses and our Community Cafe.
Conference Room
The centre has a large purpose built conference room with comfortable seating, a kitchen and buffet facilities. Modern projection equipment, TV/video/DVD players and flipcharts are available for use. The conference suite is complemented by in-house IT facilities when required. The room can also be divided into two separate meeting rooms.
Sensory Suite
Is open to all local residents and groups who wish to use it. The facility uses the latest technology to provide children and young people with a number of sensory stimulants, including light, sound, a heated water bed and aromatherapy. The room can be enjoyed by all ages for relaxation and therapeutic purposes.
Art & Design Room
The centre has an Ofsted registered purpose built multi-use art & design studio with ample storage and non slip floors.
Astro Pitch
The centre has a full sized, fully floodlit Astro Pitch, with a 'new' style playing surface. This can be hired out to anyone.
Who to contact
- Telephone
- 0161 946 9520 0161 946 9520
- email@example.com
- Website
- https://www.benchillcommunitycentre.co.uk/
- Scan to visit this website
Where to go
- Address
Benchill Community Centre
Benchill Road
- Postcode
- View M22 8EJ on a map
Last Updated
Last updated: