Human monoclonal antibody ustekinumab is a novel Crohn's disease (CD) treatment blocking pro-inflammatory cytokines interleukin-12 and 23. The study's objective was to assess cost-effectiveness of ustekinumab in moderate to severely active CD in Sweden.
A cost-effectiveness model with an induction phase decision-tree structure and a maintenance phase Markov cohort structure was constructed. CD was represented by five health-states: remission, mild, moderate-severe, surgery and death. Ustekinumab was compared to adalimumab in patients who had failed conventional care, some of which had tried TNF-alpha-inhibitor(s) without experiencing treatment failure or side effects ("conventional care failure population") and to vedolizumab in patients previously failing TNF-alpha-inhibitor treatment. Discontinuation probabilities, utilities and ustekinumab induction efficacy were sourced from phase-III trials. Maintenance and comparator efficacy came from network-meta and treatment-sequence analyses. Resource use and unit costs were derived from literature and validated by clinical experts. The analysis had a societal perspective, a life-time time-horizon, and 2-year treatment duration. The results robustness was tested in univariate and probabilistic sensitivity analyses. Cost-effectiveness was estimated using quality-adjusted life-years (QALYs).
Ustekinumab dominated adalimumab in conventional care failure population (costs: − €6984, QALYs: + 0.232). In TNF-alpha-inhibitor failure population ustekinumab accrued 0.133 more QALYs than vedolizumab, yielding a €30,282 incremental cost-effectiveness ratio. Results were sensitive to decreasing the time horizon and increased treatment duration. At Swedish reference willingness-to-pay of €63,000 (SEK 600,000), ustekinumab had 94% probability of being cost-effective versus adalimumab, and 72% versus vedolizumab.
Results indicate ustekinumab dominates adalimumab in conventional care failure population, and is cost-effective versus vedolizumab in TNF-alpha-inhibitor failure population.
Crohn's disease (CD) is a relapsing–remitting inflammatory bowel disease which mainly affects the gastrointestinal tract. Common symptoms include abdominal pain, fever, bowel obstruction and diarrhoea with passage of blood or mucus, or both . Disease complications include malnutrition, fistulas, fissures and abscesses . Approximately 20,000 people in Sweden are affected by CD , with around 10 new cases per 100,000 person-years . There are indications that CD incidence and prevalence are increasing [5–10] with most patients being diagnosed between the ages of 15 and 30 . The disease is associated with significant treatment costs, productivity losses and a substantial quality of life impact [3, 11]. The annual per patient cost of CD in Europe has previously been estimated between €6024 and €22,581. The costs were related to primary and secondary care, medical and surgical hospitalization, and labour force non-participation [12–14]. A Polish study from 2016 estimated the annual indirect costs at around €5550 per patient . The cost of CD is expected to increase due to the shift from hospitalisation and surgery towards biologic therapy use, shown in the COIN study . Reported health related quality of life (HRQoL) is significantly lower in CD patients as compared to normal populations . It has been estimated that more than 20% of Crohn's disease patients will require surgery within 5 years of diagnosis, and approximately 40% within 10 years . Common CD surgeries include strictureplasty, resection, and colectomy .
There is no cure for CD, but a variety of disease managing, often long-term, treatments are available . Biological treatments including tumour-necrosis-factor (TNF)-alpha inhibitors such as adalimumab and infliximab have significantly improved CD management, especially in patients who have failed conventional treatments (e.g. steroids, 5-aminosalicylic acid, and immunomodulators) . However, approximately one-third of patients fail anti-TNF treatment . Monoclonal antibodies, for instance biologic agent vedolizumab, have been shown to be effective in TNF-alpha inhibitor non-responders, patients with contraindications to TNF-alpha inhibitors, and in patients who lose response or develop intolerance to such agents . The human monoclonal antibody ustekinumab is a novel treatment option in CD which blocks the pro-inflammatory cytokines interleukin (IL)-12 and IL-23. The safety and efficacy of ustekinumab as an induction and maintenance therapy in moderate to severe CD has been evaluated and established in three phase 3 trials (UNITI-1 , n = 741; UNITI-2 , n = 628; and IM-UNITI [24, 25], n = 388). In the induction trials (UNITI-1 and UNITI-2), ustekinumab was found to produce significantly higher clinical response and remission rates compared to placebo both in patients who had failed conventional therapy and patients who had failed treatment with TNF-alpha inhibitors [23, 24]. Ustekinumab has been approved in the European Union for the treatment of moderately to severely active CD in patients who have an inadequate response with, or have lost response to, or are intolerant to either conventional therapy or a TNF-alpha inhibitor, or have medical contraindications to such therapies .
The objective of this study was to assess the cost-effectiveness of ustekinumab as a treatment of moderate to severe Crohn's disease in Sweden. The cost-effectiveness of ustekinumab was investigated in two populations versus the relevant comparator in each population. TNF-alpha inhibitor adalimumab was the comparator in patients who had failed conventional care, some of which had been exposed to TNF inhibitor treatment without experiencing treatment failure or unacceptable side effects ("conventional care failure" population). The monoclonal antibody vedolizumab was the comparator in a population of patients who previously failed TNF inhibitor treatment ("TNF-alpha inhibitor failure" population).
Previous cost-effectiveness studies of ustekinumab in Crohn's have been undertaken in British  and Polish  settings. Considering that cost-effectiveness analyses are highly contingent on local specifics such as cost and utility data, incidence and prevalence, as well as the health care system and clinical practice, the previous ustekinumab analyses are insufficient to draw conclusions for a Swedish context. Scandinavia sees the highest incidence and prevalence rates of Crohn's in Europe , which highlight the value of evaluations of novel treatment options. The adaptation of the model to a Swedish context included adding productivity costs. A societal perspective captures the indirect costs of CD, which in addition to constituting a substantial proportion of the total costs, reflect the severe impact on Crohn's patients' everyday life.
This analysis aims to add to the understanding of the treatment possibilities and to enable future comparisons in a population with a considerable unmet need.
The two additional health states are surgery and death. The surgery state consists of patients who receive surgical treatment for their CD. Death may occur from any health state. The cycle length used was 2 weeks, and the model had a life time horizon (60 years) in line with Bodger et al. .
All patients enter the model in the moderate to severe health state. The patients initiate biologic induction therapy (Table 1), after which responders move to biologic maintenance treatment. Non-responders following the initial induction dose move either to receive a second induction treatment dose, or to non-biologic standard of care, defined as a combination of corticosteroids and immunosuppressants. Details of the initial and second induction doses are presented in Table 1. In the base case analysis, response was defined as a decrease in CDAI score of at least 100 points. The patients who respond to the second induction dose move to biologic maintenance treatment, whereas non-responders move to standard of care.
The duration of the induction is 8 weeks for ustekinumab, 4 weeks for adalimumab and 10 weeks for vedolizumab.
In the maintenance phase, patients move between the health states depending on their level of treatment response in the induction phase and according to treatment transition probabilities.
The analysis compared ustekinumab to adalimumab in a conventional care failure population, and to vedolizumab in a TNF-alpha inhibitor failure population. Adalimumab is indicated in Sweden for moderate to severely active CD in adult patients who failed to respond despite complete and adequate treatment with corticosteroids and/or immunosuppressive therapy, or who are intolerant or have medical contraindications to such treatment . Vedolizumab is indicated in Sweden for adult patients with moderate to severe CD who did not respond satisfactorily, demonstrated a decreasing response or were intolerant to conventional therapy or a TNF-alpha inhibitor .
The population relevant for ustekinumab in Swedish clinical practice would likely be patients with no initial response (primary non-response) or subsequent loss of response (secondary non-response) to a first line TNF-alpha inhibitor. The low price following the introduction of biosimilars in practice made infliximab the first TNF-alpha inhibitor option for CD in Sweden. At primary non-response to infliximab, many patients would receive vedolizumab, as it has a different mode of action. At secondary non-response, many patients would receive another TNF-alpha inhibitor such as adalimumab, with the purpose of regaining the initial response .
As there are no clinical trials with head-to-head evaluations of biologic treatments in moderate to severe CD, an indirect comparison was undertaken of randomized clinical trials (RCTs) of all comparators of interest. A systematic literature review in accordance with NICE guidelines was conducted, identifying all relevant studies on clinical data . 41 publications reporting results from 31 different RCTs met the inclusion criteria. Network meta-analyses (NMAs) of short-term efficacy (probabilities of response or remission) for the induction phase were conducted for each population using a Bayesian framework . As the identified maintenance trials were deemed not comparable for an NMA, comparative efficacy for the maintenance phase was estimated by means of a treatment sequence analysis, considering both induction and maintenance data. The objective of the NMA was to evaluate the relative efficacy of ustekinumab in moderate to severe CD in the previously discussed populations versus adalimumab and vedolizumab. The NMA conducted separate analyses for CDAI 70, 100 and 150. Induction phase trials were found similar enough to be pooled in a standard NMA, whereas the maintenance data alone was found non-comparable due to statistical heterogeneity and as the placebo arms differed too much. Maintenance efficacy is conditional on induction phase efficacy, and therefore the full treatment pathway needed to be considered, as the placebo effect sizes from the induction trials were deemed considerable. To account for treatment history, the treatment sequence analysis included induction and maintenance data for each of the interventions. The probability of responding at the end of the induction was multiplied with the conditional probability of maintaining response until the end of maintenance.
Similar assessment times in the induction trials were selected for each intervention in line with the primary endpoints of each trial included in the analysis. The NMA used a Bayesian hierarchical model, which preserved the randomization of each trial. Relative goodness of fit of the developed fixed- and random-effects models was assessed using the deviance information criterion (DIC). To achieve data driven results, in the base case analysis, non-informative prior distributions were used for unknown parameters (normal distributions with mean 0 and variance of 10,000 for treatment effects and uniform distributions for the between-trial standard deviation with range [0, 2] for binary outcomes). The NMA was performed in WinBugs using the Markov Chain Monte Carlo (MCMC) simulation method .
The inclusion and exclusion criteria in the identified vedolizumab [38, 39] and ustekinumab [23, 24] induction trials reflected the entire TNF-alpha inhibitor failure population, as they included both primary (initial non-response) and secondary (subsequent loss of response) non-responders to TNF-alpha inhibitors. Conversely, of the included adalimumab trials [40–42], one excluded TNF-alpha inhibitor primary non-responders , one included patients who had failed or were intolerant to one TNF-alpha inhibitor (infliximab) , and one excluded patients previously exposed to TNF-alpha inhibitors . In accordance with the ustekinumab trials, and based on the available data for the comparators, vedolizumab was chosen as the comparator in a TNF-alpha inhibitor failure population, and adalimumab was chosen as the comparator in a conventional care failure population.
The only infliximab induction study identified as plausible for the comparison based on the inclusion criteria was a 20 year old, relatively small (n = 108) phase-II study . There was a high level of missing data in the placebo arm (12%) classed as non-response, and the study observed an inverse dose response, i.e. higher effect in the lower infliximab doses. In addition, the magnitude of the observed results was never repeated in subsequent studies . As this resulted in significant uncertainty in the indirect comparison it was decided not to include infliximab as a comparator.
Induction efficacy data for ustekinumab were sourced from the two induction trials UNITI-1  and UNITI-2 , and induction efficacy for the comparators was based on the NMA. Induction probabilities of response and remission for adalimumab and vedolizumab were derived by applying odds ratios (ORs) calculated in the NMA to ustekinumab induction results. Induction transition probabilities were calculated from the rate of remission (α), the rate of response (β), and the percentage of responders who remain in the moderate to severe state (γ) for the respective state following Equation 1 (induction transition probabilities).
The rates of response and remission for each comparator and population are presented in Table 2. The percentage of responders who remain in the moderate to severe state (4.7% in the conventional care failure population and 6.0% in the TNF-alpha inhibitor failure population) was sourced from the ustekinumab maintenance trial [24, 25], and assumed to be the same for all treatments. The induction rate of surgery was assumed to be 2.0% . Efficacy rates for the responders to the second induction dose were sourced from the ustekinumab  and vedolizumab  clinical trials, whereas the adalimumab rates were sourced from two efficacy studies  (Table 2).
The maintenance efficacy for all treatments was based on the treatment sequence analysis. The distribution of patients across the health states at the beginning of the maintenance phase was defined using the proportion of patients in remission and response at the end of the induction phase. Once the starting distribution was completed, a transition matrix for transitions between the CDAI health states (remission, mild and moderate to severe) was applied for each treatment, and for each cycle until the end of the treatment duration. The transition matrix was calculated using Microsoft Excel tool Solver which derives transition probabilities to minimise Eq. 2 below, i.e. the difference between the calculated distribution of patients at the end of the maintenance phase, and the distribution predicted by the NMA.
Patients may discontinue treatment due to lack of efficacy with treatment specific cycle probabilities derived from clinical trials; ustekinumab data is sourced from IM-UNITI [24, 25], adalimumab data is sourced from infliximab trial ACCENT I  due to lack of available data and vedolizumab data is sourced from GEMINI II . The cycle probabilities of discontinuation were applied to the proportion of patients in the moderate to severe health state, as it was assumed that this was the state patients would be in if there was a lack of efficacy. The percentage discontinued were as follows: ustekinumab: 10.6% (standard dose), 11.4% (escalated dose), adalimumab: 8.1%, vedolizumab 37.7% (standard dose) and 31.2% (escalated dose). The model used an annual rate of surgery of 7.0% and post-surgery transitions were sourced from a previous Markov cost-effectiveness analysis of biological therapy in CD .
Tables 1 and 2 presents the induction and maintenance dosages of all comparators and Table 3 contains the population specific patient characteristics. Subcutaneous injections (SCs) were assumed to be administered in-hospital (with a corresponding administration cost) during the induction phase, and at home by patients themselves (at no administration cost) in the maintenance phase. Intravenous infusions (IVs) were assumed to always take place in-hospital. The base case allowed dose escalation due to loss of response throughout the duration of treatment, with cycle probabilities of dose escalation of 2.0% for ustekinumab and vedolizumab  and 3.0% for adalimumab .
50% of the patients on biologic treatment were assumed to receive standard of care in addition to their biologic treatment. In the base case analysis, all patients switched to standard of care treatment after 2 years, on which they remained for the duration of the simulation or until death. To reflect that post-treatment efficacy declines gradually, the transition matrices converged from biologic to standard of care transition probabilities over a treatment specific period of time based on the respective trials [24, 39, 48].
Health state specific utilities were sourced from the ustekinumab induction and maintenance trials [23–25] and mapped from inflammatory bowel disease questionnaire (IBDQ) score into EQ-5D values . The resulting utilities were 0.80 in the remission state, 0.68 in the mild state and 0.55 in the moderate to severe state. The surgery state utility was assumed equal to the moderate to severe utility weight. The adverse events included were chosen based on expert opinion and the clinical trials of the comparators [23, 24, 39–42, 49]. Adverse events and the associated probabilities and disutilities are presented in Table 4.
For the purpose of this manuscript, costs have been converted from Swedish kronor (SEK) to euro (€) using the average 2016 European Central Bank (ECB) exchange rate (0.1057) . All costs are presented in 2016 €.
The analysis employed a societal perspective, thus both direct and indirect costs were considered. Direct costs included drug costs, resource use in terms of in- and outpatient care and diagnostics/imaging, treatment administration, adverse events and surgical complication costs. The drug prices were sourced from the Swedish Dental and Pharmaceutical Benefits Agency (TLV) . The unit cost of ustekinumab 90 mg was €3546, adalimumab 40 mg €533 and vedolizumab 300 mg €2334. An IV administration cost of €257 was sourced from a regional price list  and applied every time a dose was intravenously administered. In-hospital SCs had an associated administration cost of €124 . Each administration occasion, regardless of dose counted as one administration in terms of costs.
Resource use costs and indirect costs in terms of productivity losses by health state were sourced from a Swedish cost study of CD  and inflated to 2016 values using consumer price index from Statistics Sweden . Unit costs of adverse events were sourced from the regional price list . The cost per surgical complication was based on the cost of additional in-patient days and outpatient attendances  associated with each respective complication. The expected number of additional days and attendances were sourced from the vedolizumab UK reimbursement submission  and validated by a Swedish clinical expert in gastroenterology. The resulting 2-week direct and indirect costs per health state are presented in Table 5.
The base case analysis compared ustekinumab to adalimumab in a conventional care failure population and to vedolizumab in a TNF-alpha inhibitor failure population. Costs and effects in terms of quality adjusted life-years (QALYs) were discounted at 3.0%, in line with Swedish health technology assessment (HTA) guidelines . To understand uncertainty, a probabilistic sensitivity analysis (PSA), one-way sensitivity analyses and analyses of structural changes were performed. The one-way sensitivity analyses tested the model outcome's sensitivity to changes in various inputs, and to changes in, for example, the time horizon and treatment duration. The structural changes tested variations in assumptions on dose escalation, health state costs, response criteria, and indirect costs. The cost-effectiveness outcome is presented using the incremental cost-effectiveness ratio (ICER).
As shown in Table 6, a patient treated with ustekinumab was expected to accrue 14.275 QALYs at a cost of €232,225 over a life-time time-horizon (60 years). The corresponding for adalimumab was 14.043 QALYs gained, at a total cost of €239,209. Thus, ustekinumab had €6984 lower costs and a QALY gain of 0.232 as compared to adalimumab in the conventional care failure population. Indirect costs were the largest cost component for both treatments, consisting of approximately 50% of total costs.
As presented in Table 6, over a life-time time-horizon a patient treated with ustekinumab was expected to accrue 14.180 QALYs at a cost of €248,745. The corresponding for vedolizumab were 14.047 QALYs gained, at a total cost of €244,721. Thus, ustekinumab had a QALY gain of 0.133 as compared to vedolizumab, at a cost per QALY of €30,282 in the TNF-alpha inhibitor failure population. Again, the largest cost component for both arms was indirect costs, consisting of more than 50% of the total.
Table 7 provides results of one-way sensitivity analyses as well as analyses of structural changes. The results were most sensitive to an increase of the treatment duration to 5 years. An increased treatment duration improved ustekinumab's cost-effectiveness versus adalimumab but increased the ICER versus vedolizumab. The exclusion of adverse events had a relatively large impact in the conventional care failure population versus adalimumab. As it was suggested by a Swedish gastroenterologist that the cost of resource use in the moderate to severe health state was not sufficiently high, a sensitivity analysis was undertaken where the cost was doubled in the health state, which improved the cost-effectiveness of ustekinumab in both populations. Other structural changes analysed were CDAI-70 as response criteria, assuming no dose escalation, assuming no effect of adverse events and using different utilities, from an alternative source . These sensitivity analyses had limited impact on the results in both populations.
To test the robustness of the results with respect to uncertainty in the model input parameters, a PSA was performed for both populations, using 1000 iterations. The cost effectiveness acceptability curves (Fig. 3) suggest that ustekinumab has a 94% probability of being cost-effective compared to adalimumab and 72% versus vedolizumab at a willingness to pay (WTP) of €63,000 (SEK 600,000) in the respective populations. This WTP level was chosen as it is commonly referred to as a reference WTP in Sweden .
Assuming a lifetime time horizon and 2-years treatment duration, the results indicate that ustekinumab dominates adalimumab in the conventional care failure population with a QALY gain of 0.232, and is cost-effective compared to vedolizumab in the TNF-alpha inhibitor failure population. The QALY gain versus vedolizumab was 0.133 and the cost per QALY was €30,282, which is below the Swedish reference WTP. The results were robust to several univariate sensitivity analyses, and the PSA. Ustekinumab was dominating adalimumab in all sensitivity analyses. Considering the Swedish reference WTP, ustekinumab was cost-effective versus vedolizumab in all one-way sensitivity analyses, with the exception of when the treatment duration was increased to 5 years and when the time horizon was decreased to 5 years. Besides treatment duration and time horizon, using different utilities and the exclusion of indirect costs had the largest impact on the results.
To our knowledge, there are no other cost-effectiveness studies of ustekinumab in moderate to severe CD in Sweden. Therefore, it is not straightforward to make a comparison to previous literature. There are no head-to-head trials between biologic agents, and there is a great variation in assumptions and data sources used by cost-effectiveness studies of biologics in CD . This results in considerable variations in the outcomes of the studies. For example, a review of the cost-effectiveness of biologics in CD patients found 12 such studies, with ICERs versus conventional care ranging from dominating to €549,335 . Another study assessed the cost-effectiveness of ustekinumab versus vedolizumab from a payer perspective in the US, in a population of TNF-alpha inhibitor naïve, non-TNF-alpha inhibitor refractory patients. Considering a lifetime perspective, vedolizumab accrued 10.461 QALYs whereas ustekinumab accrued 10.326 with incremental costs of $55,523 in favour of vedolizumab . This comparison was done in a different population than ours, and little information on the assumptions was presented. A straightforward comparison on the difference to our outcome is therefore impossible. Another analysis of ustekinumab's cost-effectiveness versus vedolizumab as a third line agent after failure with two TNF-alpha inhibitors found that vedolizumab had higher costs of $168,648 as well as a larger QALY gain of 0.029, resulting in an ICER of $5,815,448 . A polish study found treatment with ustekinumab after failing one TNF-antagonist associated to a QALY gain of 0.349 and an ICER of €18,878 compared to adalimumab after infliximab failure . The variations in outcomes of cost-effectiveness analyses of biologics in CD emphasise the importance of further research in the field, and a need for a greater consensus over model design and assumptions.
Similar model structures as the one utilized for this study have previously been used in HTAs of biological CD treatments [29, 63, 70, 71]. The analysis is based on the best available clinical evidence and publicly available data. The ustekinumab induction trials (UNITI-1 and UNITI-2) had high internal validity. As a means of improving flexibility, the model allowed continued induction response assessment. As there are no head-to-head trials between biologics in CD, efficacy between the comparators had to be indirectly estimated. NMAs were performed for the induction phase and treatment sequence analyses were utilised for the maintenance phase for the respective populations. The clinical endpoints in the induction trials were estimated at week 6 for ustekinumab and vedolizumab, and week 4 for adalimumab. The efficacy assessment time points in the NMA were in line with the included studies .
Previous failure to TNF-alpha inhibitor treatment was found to impact the results of the NMA. Therefore, separate analyses were undertaken between trials including conventional care failure patients and TNF-alpha inhibitor failure patients. Moreover, a sensitivity analysis was undertaken in which conventional care failure inputs were replaced with inputs for patients truly naïve to biologics, providing evidence of robustness to the results. To further validate the results of the NMA, and to investigate potential sources of bias, several other sensitivity analyses were undertaken which supported the base case outcome .
A common issue in performing indirect comparisons is heterogeneity between the source trials. The placebo arms were not comparable across the maintenance trials, and could therefore not be used as a common comparator to anchor the indirect comparison, rendering a traditional NMA impossible. Moreover, statistical analyses revealed significant levels of heterogeneity. As often in maintenance trials, patient selection was based on induction response to the evaluated treatment. Additionally, the patient profiles in terms of previous TNF-alpha inhibitor treatment failure differed over the trials. The adalimumab trials only included secondary non-responders, whereas the vedolizumab and ustekinumab trials included primary non-responders as well. As the latter inclusion criteria allowed patients with more severe disease, the effect of ustekinumab and vedolizumab risked being underestimated compared to adalimumab in an indirect comparison. As the maintenance effect is a product of initial treatment effect, the full treatment pathway had to be considered. A treatment sequence analysis was therefore the most plausible option to obtain long-term relative efficacy. Not only did this increase the comparability between maintenance trial placebo arms, it also allowed an evaluation of effect over the full treatment sequence .
The first cost-effectiveness model for CD was developed by Silverstein et al.  using data from an observational US cohort (1970–1993) from Olmstead County. It was published in 1999. More recently, in 2009, Bodger et al.  adapted the Silverstein model to a UK context. CD models have since then been developed for three NICE appraisals. Namely appraisals of infliximab and adalimumab , of vedolizumab , and of ustekinumab ; the latter being the model which this study is based on. The previous models' limitations include not capturing the relapsing–remitting nature of CD, overly simplifying surgery by disregarding that subsequent surgery often is contingent to first surgery, and using too short time horizons to capture long-term outcomes. As CD is a chronic condition, such outcomes are important to understand the full implications of the disease.
The Bodger et al. model structure on which this model builds have some limitations. It does not allow for treatment sequencing or re-treatments. This is less critical in our analysis, as the populations evaluated are not treatment naïve, but have experienced either conventional care or TNF-alpha inhibitor treatment. Thus, we indirectly model treatment sequences, but with initial treatment taking place outside of the simulation, reflected in the patient data. Additionally, properly modelling treatment sequences would require currently unavailable efficacy data, or ill-founded assumptions. Although the model allows for maintenance transitions from the moderate to severe health state, the structure does not capture increased relapse risk after discontinuing biologics [28, 72, 73], and—as previously discussed—does not consider the impact of surgery on future surgeries.
In the development of the ustekinumab model, such limitations were considered. For example, in the model patients can transition from the moderate to severe health state in the maintenance phase, thus reflecting that CD is a relapsing–remitting disease. Developments of the surgery modelling was explored, but resulted in non-intuitive outcomes. Other model developments to overcome previous limitations included differentiating the induction length of the comparators, adding the possibility to test different treatment lengths, and—specifically based on input from three health economic experts and a leading clinician—including a gradual decline in post-treatment efficacy in the maintenance period.
The Solver approach to estimate transition probabilities have a number of limitations, as pointed out by the ERG . The approach is contingent on constraints and starting values, which although based on a previous NICE submission , were criticized for increasing uncertainty while having a substantial impact on the transition probabilities and subsequently the cost-effectiveness. Previous criticism was however accounted for by the inclusion of additional calibration constraints.
To validate the model, a comparison was done between model outcomes and the predicted outcomes of the treatment sequence analysis. The comparison concerned 1-year outcomes of the proportion of patients ending up in each health state. The model outcomes were very close to the predicted outcomes—with a slight bias against ustekinumab in the conventional care failure population .
Patients who did not respond to the initial and second induction doses were assumed to remain in the moderate to severe health state and spend the remainder of the simulation on standard of care. This is a simplification of clinical practice, but was deemed the most reasonable assumption in absence of adequate data. Some inputs were unavailable for a Swedish setting, for instance no adverse event risk data in Swedish CD patients was identified. Therefore, it was assumed that the same risk as estimated in moderate to severe CD patients in the UK apply to Swedish patients. Modelling assumptions inevitably produce uncertainty, but in order to reduce it to the greatest extent possible, assumptions related to data gaps, model inputs, and treatment regimens were validated by Swedish clinical experts in gastroenterology.
As this study was designed to capture Swedish health economic circumstances, the generalisability of the conclusions to an international context is limited. However, the observed cost-effectiveness outcomes are likely similar within other regions with similar CD incidence and prevalence, and comparable health care systems such as for instance, the other Nordic countries.
In conclusion, based on available evidence, and while acknowledging the inherent limitations of cost-effectiveness modelling; from a societal perspective, ustekinumab is dominating adalimumab in Sweden in patients who failed conventional treatment. Moreover, the results indicate that ustekinumab is likely to be cost-effective versus vedolizumab in patients who previously failed treatment with TNF-alpha inhibitors.
All authors have made substantial contributions to the study design, and to the acquisition and interpretation of the data. All authors have contributed to the drafting and critical revision of the manuscript, and have given final approval to the version to be published. Each author has participated sufficiently in the work to take public responsibility for the content, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.
Authors' declaration of personal interests.
AHH, LK and FB are employees of Quantify Research which was contracted and paid by Janssen-Cilag to conduct the Swedish model adaptation. The authors did not receive direct payment as a result of this work outside of their normal salary payments.
FB owns stocks in Quantify Research.
CA and IS are employees of BresMed Health solutions which was contracted and paid by Janssen-Cilag to develop the original cost-effectiveness model. The authors did not receive direct payment as a result of this work outside of their normal salary payments.
DE and ATB are employees of Janssen-Cilag.
This study was funded in full by Janssen-Cilag AB.
Crohn's & Colitis Foundation. Intestinal complications. 2012. http://www.crohnscolitisfoundation.org/resources/intestinal-complications.html?. Accessed 08 May 2017.
Ludvigsson J, Myrelid P, Årsrapport SWIBREG [Annual Report], SWEBREG, Swedish Inflammatory Bowel Disease Registry, Editor. 2015. http://www.swibreg.se/wp-content/uploads/2015/11/SWIBREG_arsrapport_2014.pdf. Accessed 30 July 2018.
ILCO, Tarm-uro och stomiförbundet. Crohns sjukdom. 2017. http://www.ilco.nu/diagnoser-och-behandlingsformer/diagnoser/morbus-crohn/. Accessed 05 May 2017.
European Central Bank. Swedish krona (SEK), SEK vs. EUR. Average 1 January 2016 to 31 December 2016. Euro foreign exchange reference rates 2017. https://www.ecb.europa.eu/stats/policy_and_exchange_rates/euro_reference_exchange_rates/html/eurofxref-graph-sek.en.html. Accessed 31 July 2018.
The Dental and Pharmaceutical Benefits Agency, (TLV). Läkemedel [Pharmaceuticals]. 2016. https://www.tlv.se/beslut/sok/lakemedel/. Accessed 31 July 2018.
Statistics Sweden, CPI, Fixed Index Numbers (1980 = 100). 2017. http://www.scb.se/en/finding-statistics/statistics-by-subject-area/prices-and-consumption/consumer-price-index/consumer-price-index-cpi/pong/tables-and-graphs/consumer-price-index-cpi/cpi-fixed-index-numbers-1980100/. Accessed 31 July 2018.
Vedolizumab for treating moderately to severely active Crohn's disease after prior therapy. Technology appraisal guidance [TA352], The National Institute for Health and Care Excellence, (NICE), Editor. 2015. https://www.nice.org.uk/guidance/ta352/chapter/3-The-companys-submission. Accessed 31 July 2018.
The Dental and Pharmaceutical Benefits Agency (TLV). Kostnadseffektiva läkemedel [Cost-effective pharmaceuticals]. https://www.tlv.se/download/18.467926b615d084471ac3396c/1510316400262/kostnadseffektiva-lakemedel.pdf. Accessed 31 July 2018.
Statens legemiddelverk [The Norwegian Medicines Agency]. Hurtig metodevurdering Vedolizumab (Entyvio) til 2. og 3. linjebehandling av moderat til alvorlig Crohns sykdom Vurdering av innsendt dokumentasjon [Health technologic assessment of vedolizumab as 2nd and 3rd line treatment of moderate to severe Crohn's disease]. 2015. https://nyemetoder.no/Documents/Rapporter/Vedolizumab%20Crohns%20-%20hurtig%20metodevurdering.pdf. Accessed 31 July 2018.


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FIRST FRIDAY ART WALK @ St. Augustine Art Galleries
Aug. 4: On the first Friday of every month, St. Augustine's art galleries welcome visitors to browse the latest art exhibits and enjoy refreshments and live entertainment at more than 26 participating galleries. Many of the featured artists are on hand to answer questions about their work. Artwalk takes place throughout St. Augustine's historic downtown area — even over the Bridge of Lions onto Anastasia Island and the beach. Old Town Trolleys and Ripley's Sightseeing Trains provide complimentary shuttle service to most of the galleries. Admission is FREE. Go www.artgalleriesofstaugustine.com for more details.
SAM PACETTI @ DOS Coffee and Wine
Aug. 5: St. Augustine musician Sam Pacetti will perform from 7 to 10 p.m. Saturday, August 5 at DOS Coffee and Wine, 300 San Marco Ave., St. Augustine. Admission is free.
THE 25th ANNUAL PUTNAM COUNTY SPELLING BEE @ Limelight Theatre
Through August 20: On Broadway in 2005, this musical comedy features an eclectic group of six students vie for the spelling championship of a lifetime. Show times are 7:30 p.m. Thursday-Saturday, with a 2 p.m. Sunday matinee at Limelight Theatre, 11 Old Mission Ave., uptown St. Augustine. Get tickets at limelight-theatre.org
Swashbucklers Pillage and Plunder for School Supplies @ St. Augustine Pirate & Treasure Museum
August 5: The St. Augustine Swashbucklers will be collecting school supplies from 10 a.m. to 3 p.m. Saturday, August 5 at the St. Augustine Pirate & Treasure Museum, 12 S. Castillo Drive, downtown St. Augustine. Purchase water balloons to soak your favorite pirate, play pirate games, go ontour with Commodore Mayhem, take pictures with pirates. Raffles will be held throughout the day and discounted museum entrance for all school supply donations.
GODSPELL @ Ponte Vedra Concert Hall
Aug. 4-6: The Apex Theatre Studio Inc., in partnership with the Ponte Vedra Concert Hall, is delighted to present "Godspell," the well-loved Off-Broadway classic that puts a contemporary spin on the Gospel of St. Matthew, live on stage at the Ponte Vedra Concert Hall on Friday, August 4 at 8 p.m. and on Saturday, August 5 at 2:00 p.m. and 8 p.m. Go to pvconcerthall.com for more details.
St. Augustine Social
For and about St. Johns County residents, St. Augustine Social is the authority on a life well lived on the first coast. Designed to engage active families and the cultured reader, our editorial highlights the stories that residents and visitors truly want to know about our town like weekend guides, hometown talent, local food flavors, home improvement, top tastemakers, interesting personalities and nationwide shopping trends available right in our backyard.
St. Augustine's Can't-Miss Spring Festivals 2020
St. Augustine Art Association Names "Cutting Edge" Honorees
10th Annual St. Augustine Film Festival Returns to the City
22 St. Augustine Talks and Tours to Get You in Touch with Nature
A Flagler Student's Guide to St. Augustine
A New Beat in the Old City
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redpajama_set_name: RedPajamaCommonCrawl


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Stuntwomen Survey: Two-Thirds Report Being Bullied Or Sexually Harassed On The Job
By David Robb
David Robb
Labor Editor
More Stories By David
Costume Shop Workers At L.A. Opera Ratify First-Time IATSE Contract
WGA West Blasts Warner Bros Discovery Moves Ahead Of Possible Writers Strike; WBD Says It's Committed To "Facilitating Greater Inclusion Of Underrepresented Groups"
WGA East Members Threaten To Strike HuffPost Unless Given A Fair Contract By Midnight Tuesday
Julie Johnson
An informal poll of Hollywood's stuntwomen has found that nearly two-thirds of the 43 respondents have been bullied or sexually harassed in the workplace. The same number said they knew of others who had experienced on-the-job bullying or harassment. More often than not, the poll found, the perpetrators were the shows' male stunt coordinators.
The independent poll, conducted by veteran stuntwoman Julie Johnson, also found that nearly 40% of the respondents had witnessed men putting on dresses and wigs to double for actresses and that 35% had witnessed "paint downs" – the application of makeup to allow a white stunt person to double for a minority actor. (Read the full survey results here.)
'Painted Down: The Movie' Clip - Recounting Black Stuntmen's Early Hollywood Struggles
The poll, which offers a rare glimpse into the lives of women who work in Hollywood's most dangerous profession, found that more than 75% of the respondents said they'd been injured on the job. Nearly 40% said they'd been injured more than three times, with two of the women saying they'd been injured "too many times to count." Two of the respondents said they'd been "intentionally injured" on the job by fellow stuntmen, while one stuntwoman reported that she'd been the victim of an attempted rape or assault in the workplace. Nearly 25% of the respondents said they sometimes feel uncomfortable or unsafe on the job.
More than half of the respondents said they don't feel they get an equal shot at "non-descript" jobs – doubling for characters whose gender is not specified in the script, such as a bank teller who is shot or a pedestrian who gets hit by a car. The vast majority of these jobs routinely go to male stunt performers.
Johnson has been a leading advocate for stunt safety and gender equality for more than 50 years. In 2013, I co-authored her biography, The Stuntwoman. She sent the survey to 164 stuntwomen, about a quarter of whom responded. On Thursday, she sent the results to SAG-AFTRA National Executive Director David White. "Over many years," she told him, "far too many of us have been subjected to bullying and sexual abuse."
Johnson is co-founder of the Stuntwomen's Association and was co-chair of the SAG Stuntwomen's Sub-Committee in 1982 when the guild authorized its first and last survey of stuntwomen. Three decades later, she thought it was time for another. She contacted the union but said she was told it would take a year, if it could get approved at all. So she decided to conduct her own.
The 1982 survey got nearly identical results. That questionnaire was sent to 85 stuntwomen – with 44 responding – one more than in Johnson's survey. Of those, 27 (61%) said they'd been sexually harassed on the job – about the same as in Johnson's survey. Safety was another key concern then, but in those waning days of the cocaine-fueled disco era, drugs were an even bigger issue. Today, two-thirds said that drugs and alcohol abuse is not an issue in the workplace. In 1982, more than half said that they'd witnessed drug dealing in the workplace, had worked with someone under the influence of drugs and had been offered drugs on the set.
Johnson said that she hopes her survey will lead to "a better understanding of our lives in this business. Producers and the union have to work closer together on our behalf. It's long overdue."
LAX Power Failure Halts TSA Screenings; Outage "Being Investigated"


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Windows and User Productivity>Windows 7/8
With Online Spreadsheet, Google Enters Yet Another Microsoft Market - 06 Jun 2006
Paul Thurrott | Jun 05, 2006
It's suddenly clear why Microsoft is so nervous about online search giant Google. Despite Google's protests that it has no interest in competing in Microsoft's key markets, Google has been busy releasing products and services the past few years that do exactly that. The latest example, Google Spreadsheets, was announced today and represents Google's second major foray into office productivity software.
Granted, the initial version of Google Spreadsheets isn't going to challenge Microsoft Excel's domination any time soon. It can't even make charts or graphs yet. But the bare-bones Google Spreadsheets package does do a few things that Excel doesn't, and it's only a matter of time before it comes with some of Excel's more widely used and desktop-oriented features.
Once again, Google is downplaying what is clearly a heated rivalry. "I see them as complementary," Jonathan Rochelle, the product manager for Google Spreadsheets told "The Wall Street Journal," referring to Google Spreadsheets and Excel. "I know a lot of users will use both." What an interesting way to characterize the situation. Currently, the majority of Excel users use Excel for spreadsheet functionality, and nothing else.
Google says that Google Spreadsheets is notable because it allows multiple users to easily work on a shared spreadsheet online, in real time, through integration with Google's GTalk IM service. "Many people already organize information into spreadsheets," Rochelle notes. "Where they're struggling is to share it." To maximize compatibility, Google Spreadsheets works with spreadsheets created in Excel and in its own format.
Predictably, Microsoft expresses no outward concern about the Google service, but you have to believe that the company's engineers are working overtime to assess the threat. "There's nothing new here \[with Google Spreadsheets\] really," Microsoft General Manager Alan Yates said. "It's like watching a time machine from ten years ago."
If there's nothing new here, then why even discuss the product? Because Google Spreadsheets, like all Google products and services, is a work in progress. As always, Google has placed an early, unfinished version of the service on the Web for users to try--although it's currently available only to a limited test group. Google will add features and functionality over time. If it's successful, Google Spreadsheets will turn into a true Excel competitor. And if not, it will simply wither in cyberspace, its fate the same as that of other failed Google initiatives.
In addition to Google Spreadsheets, Google recently launched or purchased office productivity products and services, including online word processor, email, IM, calendar, desktop search, and Web page and blog creation tools. Virtually all of these products and services are still fairly rudimentary compared to the well-polished desktop-oriented tools that Microsoft creates, but because Google's offerings are made available online and for free, they can be updated quickly and regularly. Microsoft has only sporadically offered those types of tools to the public online and for free in the past, primarily through its MSN unit. Not coincidentally, those offerings were pulled into the Windows Division last year and are now being rolled out as Windows Live services.
So is Microsoft justified in its fear of Google? Most likely, yes. Google is flush with cash and, despite its public pronouncements, seems to have little problem jumping into major Microsoft markets. And let's face it, in recent years Microsoft hasn't exactly been the bully it used to be because of its ongoing antitrust concerns. When Adobe threatened to sue the company over its support of PDF--a technology that Adobe licenses to numerous other companies for free--Microsoft simply caved, removing both PDF and its own competitive format, XML Paper Specification (XPS) from Windows Vista and Office 2007.
Microsoft Edge Downloads Updated for Azure AD Sign-In & Sync
How to Approach the Windows 7 to 10 Migration
Chromium Based Microsoft Edge Download Ready for Enterprises
Microsoft Results to Get Lift From Office, Windows Cloud Bundle


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Reviewing The Chilli Pickle in Guildford
PUBLISHED: 10:41 13 November 2018 | UPDATED: 10:50 13 November 2018
It feels like walking into The Beatles' Sgt Pepper's Lonely Hearts Club Band album (Photo by The Chilli Pickle)
Having bloomed in Brighton's restaurant scene over the past decade, The Chilli Pickle opened its second site in Guildford this summer
Having begun life as a small 50 cover restaurant hidden away among Brighton's cobbled lanes, the success of The Chilli Pickle has led to ambitious plans to grow it across the south east of England.
The concept was launched by husband and wife team, Alun and Dawn Sperring, whose aim has always been to recreate the flavours of India, which have long been their obsession and inspiration, with the ingredients available on their doorstep.
This passion has led to the Brighton restaurant holding two AA rosettes since 2009 and a Michelin Bib Gourmand since 2010 – and, while the south coast town's restaurant scene is buzzing these days, they were there from the start.
So, why am I writing about all of this in Surrey Life? Well, the first of their new restaurants opened in Guildford this summer. It's a huge 150 or so cover venue spread over two dining room floors at the top of the High Street, near G Live.
Having read the back story, I'm a little surprised by the scale and ambition of this independent's new home when we arrive. They're clearly not doing things by halves. The walls are a psychedelic kaleidoscope of colour, the background music flits between The Beatles, Bob Dylan and more traditional tunes and it makes for a bright and breezy welcome. It feels like you've walked into The Beatles' Sgt. Pepper's Lonely Hearts Club Band album.
Sri Lankan seabass curry (Photo by Matthew Williams)
Settled at our table, we quickly get down to the business of pouring over the food and drink options. The impressive drinks list celebrates their Sussex roots, with the likes of Trenchmore Farm's Silly Moo Cider and Goring Brut from the Wiston Estate, but also features well-picked international flavours, intriguing cocktails and pairing recommendations.
We'll be staying away from those cocktails on this occasion, as we've got our three-year-old daughter in tow, who is as fascinated by the decorations as she is the children's drawing set on the table.
Poppadoms arrive with a rainbow array of chutney, pickle and onion salad on a silver platter. Both our starters are exciting little introductions to what the restaurant is all about. The pana puri, an Indian street snack consisting of crispy shells filled with potato and chickpea salad alongside a tamarind water with chilli to drizzle into it, are lovely little flavour explosions. The samosa chat is alive with red onion, ginger, sweetened soya yoghurt, kaleidoscope chutneys and sev (crunchy noodles) – you discover something different with every mouthful.
Right up until the moment our order is taken, I'm sure I'm going for the beef short rib madras but 'mixed grill' comes out of my mouth instead. Not something I'd normally go for, but I'm intrigued by the combinations on offer… I'm not completely won over by it, if I'm honest, although hats off to the pepper chicken seekh and smoked aubergine riatta.
Oh well, it's an excuse to visit again and with Michael Bremner, owner of Brighton's current top-rated restaurant (according to the 2018 Brighton Restaurant Awards), 64 Degrees, recently recommending the madras dish, I feel rather bound to.
There is a moment of confusion as the wrong main course is delivered to Sylviane, but this is swiftly spotted and rectified by the manager – and the dish, ultimately, is a hit with its whole sea bass swimming in waves of nuanced flavour.
All the while, our three-year-old daughter is absolutely demolishing her mild kids chicken thali with rice, riatta, chutney and baby naan and poppadum. She loves the fun element of being able to dip, mix and enjoy each component - while multi-tasking and colouring in the menu with the pencils provided. Meanwhile, my dessert of coal roasted fresh pineapple with chilli and stem ginger glaze and coconut sorbet is an absolute winner. I could eat bowls full of that one, daily.
Overall, I really admire The Chilli Pickle's story and, while there's probably still a bit of time before the Guildford restaurant reaches the magical levels of its Brighton counterpart, there's a passion and ambition behind the place that seems to indicate they'll get there. It's already a colourful adventure.
The Chilli Pickle, 219 High Street, Guildford GU1 3BJ; thechillipickle.com; 01483 388101


Goblinz Studio has announced the upcoming release of Robothorium, a sci-fi tactical RPG that involves robots rising against their human oppressors. The game is heading to the Nintendo Switch on January 31.
Robothorium seems like it has a little of everything on offer, described as a cyberpunk dungeon crawler with turn-based fights. In the game, your choices will have a direct impact on your revolution against humankind. You'll need to hone your skills for deep strategy, crafting, and party-based management if you want to win this war.
The game features turn-based fights, with eight classes of robots. Each class has its own synergies as you face off with plenty of enemies designed to use their unique mechanics to defeat you.
As you manage your troop of robots, you can choose your allies and manage your reserve. You'll also have the ability to craft and gather powerful items, so you can upgrade your talents. There's online multiplayer to boot – which only makes sense in a futuristic game about uprising robots.
Robothorium will hit this Switch on January 31 2019. Are you ready to rise against all humans? Let us know your thoughts in the comments section.


A necklace with a brand new charm designed in collaboration with METAvivor. Featuring the new METAvivor Charm on an Apex Chain in your choice of gold or silver.
Moon and Lola will donate 20% of the proceeds from sales of this necklace directly to METAvivor's cause.


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Researchers Surprised to Find Number of Leopards in Northern China on the Rise
TOPICS:EcologyUniversity of CopenhagenZoology
By University of Copenhagen October 27, 2020
Most of the world's leopards are endangered and generally, the number of these shy and stunning cats is decreasing. However, according to a recent study by a researcher from University of Copenhagen and colleagues from China, leopard populations in northern China are on the mend. Discover why below.
Leopards are fascinating animals. In addition to being sublime hunters that will eat nearly anything and can survive in varied habitats from forests to deserts, they are able to withstand temperatures ranging from minus 40 degrees Celsius during winter to plus 40 degrees in summer.
Despite their resilience, the majority of leopard species are endangered. Poaching and the clearing of forest habitat for human activities are among the reasons for their global decline.
But in northern China — and specifically upon the Loess Plateu — something fantastic is occurring. Numbers of a leopard subspecies called the North Chinese leopard have increased according to a new study conducted by researchers from the University of Copenhagen and their colleagues in Beijing.
"We were quite surprised that the number of leopards has increased, because their populations are declining in many other places. We knew that there were leopards in this area, but we had no idea how many," says Bing Xie, a PhD student at UCPH's Department of Biology and one of the researchers behind the study.
Photo of a North Chinese leopard in Loess Plateu, caught on camera. Credit: Beijing Normal University
Together with researchers at Beijing Normal University, she covered 800 square kilometers of the Loess Plateu between 2016 and 2017. The just-completed count reports that the number of leopards increased from 88 in 2016 to 110 in 2017 — a 25 percent increase. The researchers suspect that their numbers have continued to increase in the years since.
This is the first time that an estimate has been made for the status of local population in North Chinese leopards.
Five-year reforestation plan has worked
The reason for this spotted golden giant's rebound likely reflects the 13'th five-year plan that the Chinese government, in consultation with a range of scientific researchers, implemented in 2015 to restore biodiversity in the area.
"About 20 years ago, much of the Loess Plateau's forest habitat was transformed into agricultural land. Human activity scared away wild boars, toads, frogs, and deer — making it impossible for leopards to find food. Now that much of the forest has been restored, prey have returned, along with the leopards," explains Bing Xie, adding:
"Many locals had no idea there were leopards in the area, so they were wildly enthused and surprised. And, it was a success for the government, which had hoped for greater biodiversity in the area. Suddenly, they could 'house' these big cats on a far greater scale than they had dreamed of."
Leopards are nearly invisible in nature
The research team deployed camera equipment to map how many leopards were in this area of northern China. But even though the footage captured more cats than expected on film, none of the researchers saw any of the big stealthy felines with their own eyes:
"Leopards are extremely shy of humans and sneak about silently. That's why it's not at all uncommon to study them for 10 years without physically observing one," she explains.
Even though Bing Xie has never seen leopards in the wild, she will continue to fight for their survival.
"That 98 percent of leopard habitat has been lost over the years makes me so sad. I have a great love for these gorgeous cats and I will continue to research on how best to protect them," she concludes.
Reference: "Elusive cats in our backyards: persistence of the North Chinese leopard (Panthera pardus japonensis) in a human‐dominated landscape in central China" by Haitao Yang, Bing Xie, Guojing Zhao, Yinan Gong, Pu Mou, Jianping Ge and Limin Feng, 21 August 2020, Integrative Zoology.
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Difference between revisions of "A. Eady and Co."
From HtownWiki
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Revision as of 23:44, 18 November 2019 (edit) (undo)
[[image:Eady1911.jpg|left|thumb|300px|''A. Eady and Co.'' advertisement, 1911]]
[[image:Eady1918.jpg|right|thumb|300px|''A. Eady and Co.'' advertisement, 1918]]
''A. Eady and Co.'' was an Auckland company selling musical instruments, phonographs and records, owned by Arthur Eady. Initially, called ''The Muscial Budget'', it had a branch in Hamilton from around 1908, run by Samuel Riley. Apparently the earliest established music store in Hamilton, it was situated just north of the [[Theatre Royal]]. In 1912, due to its popularity, it opened another shop in Victoria St. It was still active in Hamilton until a little after 1930.
[[category:Musical Instrument Stores]]
[[category:Music Stores]]
A. Eady and Co. advertisement, 1911
A. Eady and Co. was an Auckland company selling musical instruments, phonographs and records, owned by Arthur Eady. Initially, called The Muscial Budget, it had a branch in Hamilton from around 1907, run by Samuel Riley. Apparently the earliest established music store in Hamilton, it was situated just north of the Theatre Royal. In 1912, due to its popularity, it opened another shop in Victoria St. It was still active in Hamilton until a little after 1930.
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Baby Blak was ushered into the rap game via fellow Philly native DJ Jazzy Jeff, one of its finest craftsmiths. He could use Jeff now.
For this double A side off his Blaker than Midnight EP, he enlists Sweden's DJ Devastate, whose production borrows heavily from some familiar sources. Blaker than Midnight owes a great deal to DJ Premier, lifting heaviy off Mos Def's Mathematics (b-side to Ms. Fat Booty) and though he mimics Primo's steez admirably, he's not breaking any ground by doing so. It suffers greatly because of it. Moves 2 Make doesn't venture that far from template, either. The man can flow over the right production; should have kept shopping for it.
The first official release from the anticipated Wu-Tang/D-Block collaboration sets the bar high for the album with Jake Uno's relentless low boom accentuated by sharp splashes of crash and ride propelling Ghostface Killah and Sheek Louch through the underground of New York and straight to your cerebral. This is a preemptive strike both teams are chomping at the bit to unleash to the streets. When they announced the collaboration last year, they were quite explicit about the fact that this record was for exactly that demographic. This joint is so thick one forgets that it's a timeless ode to rolling up on honeys in the club. It's that dope.
Drag and drop this into the "fire" section of your subcrates.
Jay-Z should pay attention to this record.
The Broad Street Bully, who is determined to return to the collective rap consciousness with a vengeance, displays that raw viciousness we have come to expect from the State Prop general. Backed by the familiar coterie (Freeway, Peedi Crack, Omilio Sparks and Young Chris), Sigel delivers his verses with an urgency further punctutated by the fact that he's staring down a two-year bid, so it's no surprise he's going in guns blazing. The Don Cheegro production – unfortunately – too closely mirrors Salaam Remi's post-90s work with Nas. We are given very little indication as to who Cheegro is. The SP team can take credit for living up to their reputation of being able to spit bars over various types of production but someone really should have tapped Cheegro on the shoulder and let him know Remi's been there, done that.
Sigel rips his rap contemporaries a new one and stakes his claim to the throne that he is no longer content with just watching.


Incorrect: Africa is clearly lacking behind [in foreign investment].
Correct: Africa is clearly lagging behind [in foreign investment].
One very controversial topic recently is how America is lagging far behind other nations in terms of quality of education.—Business Today.
U.S. lagging behind on gender equality.—CNN.
Customers with mental illness are lacking services due to decreased funding available to the local CMH.
Maybe Merriam Webster has it.
2: to stay or fall behind.
It occurs to me that "to lag" already implies "behind", which is really added to the idiom only for emphasis. For instance, you could say, "America is lagging other nations in terms of quality of education," and the meaning is not different than "lagging behind." If you want to suggest the degree of lag, however, "lagging far behind" works well, although "much lagging" or some other construct could work, also.
I agree with David–the word "lagging" usually does not need "behind" to explain such situations.
I feel Lagging Behind is necessary as compared to just Lagging because Lagging has multiple meaning, so using just lag would not necessarily mean the same as using Lagging behind.


Wow I'm behind with sharing weddings, the whole pregnancy and then having two kids thing has really been sucking my time! But even if this wedding was a year ago, it doesn't change how super fun and beautiful it was.
Rory & Emily got married at the Gundaroo Soldiers Memorial Hall and then had their reception at the always amazing Grazing. You know it's a good wedding when almost all the guests break into song together with the enthusiasm one usually reserves for singing in the shower.
Thank you Emily & Rory for choosing us to take your photos, you made everything so easy, relaxed and fun. We're so thankful that we got to be apart of your wedding day!
Thank you Annika for your second shooting, you're the shampoo to my conditioner.


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Saubermacher rumoured to acquire AVE
Styrian waste management and recycling firm Saubermacher Dienstleistung-AG reportedly wants to acquire Upper Austrian waste management firm AVE, a subsidiary of Upper Austrian energy provider Energie AG Oberösterreich (EAG).Business magazine trend reported the news today (Mon), but EAG General Director Leo Windtner said the report had no basis in fact.He said: "AVE's continued consolidation is our priority. We are on the way to reaching our desired goals within two years." He added that AVE was considering the acquisition of Styrian waste management company UEG, which went bankrupt in February.AVE's turnover of 411.7 million Euros in 2008 declined to 397.5 million Euros in 2009, but all firms in the sector had been negatively affected by recession, Windtner noted, adding that a competitor that had told the media it was interested in AVE was hardly a potential cooperation partner.He added: "AVE is basically better than other firms in the sector, is once again number one in Austria after a difficult period and is expanding into Eastern Europe."Trend quoted Saubermacher chief Hans Roth as saying that the acquisition of AVE would be the highlight of his life's work.Saubermacher would become Austria's largest waste management firm if it acquired AVE following its takeover of Rumpold for 65 million Euros in 2006, the magazine added.Saubermacher, founded in 1979, had turnover of 246 million Euros and 3,700 employees in 2009.
Tags acquisition, AG, AVE, Euros, firm, magazine, management, Saubermacher, waste, Windtner
← First barrier-free driving school opens its doors → Catholic Church's Klasnic pick causes a stir


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Gunners
Emery on why Ozil wasn't in the Arsenal squad
Arsenal Emirates Stadium Game Week Ozil Unai Emery
August 26, 2018 GunnersLeave a Comment on Emery on why Ozil wasn't in the Arsenal squad
Unai Emery was quizzed about Mesut Ozil's absence from the matchday squad against West Ham on Saturday as we claimed our first win of the season.on claims that Mesut Ozil left training after being told he wouldn't play today…Maybe in English it is difficult to explain, but first, why is this information [being reported]? It isn't true. That information needs first to be true. Who is starting to telling you or us this information? You ask me, or the doctor, or the club. He was sick yesterday. He spoke with the doctor and with me, and decided not to play today. But he did not leave training [due to that], but because he was going to his home, because he was sick.
on whether he would have played if he was not sick…
He was sick and today, he was sick. He left to his house and I said to him, to come [to the match] if he feels better and he feels better today and before the match he is with the team and with me.
on what type of sickness he has…
When you are sick… I don't know how I can explain in English. In Spanish it is 'catarro'.
Translator: He is blocked up, he's got a cold.
UE – He is bad with sick. It is not a problem with the player, it is not true this information. So ask the doctor and the doctor can explain better!
Arsenal come from behind to beat West Ham as Unai Emery picks up first Premier League win
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Three academy players sign pro contracts
August 23, 2018 Gunners
Bordeaux consider Claudio Ranieri as new manager after talks with Arsenal legend Thierry Henry stall
Aaron Ramsey to Follow Ozil's Example and Delay Decision on His Arsenal Future Until January
August 29, 2018 August 29, 2018 Gunners
Mesut Ozil Back to Training, Does he hold enough fire power to get us over the line against Liverpool ??
Our Cap. is fit to Start. Do you want him @ Starting Lineup ???
Kieran Tierney Opens Up on £25m Move to Arsenal After Bidding Celtic Teammates Farewell
Arsenal Star Believed to Be Back in Training After Mystery Illness Forced Absence From West Ham Win
Gunners	| Theme: News Portal by Mystery Themes.


Look at any shopping website and you'll find more tablets than your average branch of Boot's. Since the success of the iPad, and the subsequent success of countless Android devices, manufacturers have been clamboring over each other to release more and more tablets. How do you choose between them all?
We've put together a quick guide to help you!
If you're using your tablet for work, the Microsoft Surface Pro 3 is your best bet. With an attachable type cover, it's more or less a laptop and a tablet in one.
It has a 12 inch display and specs comparable to a MacBook if you're willing to pay enough. With multitasking functions and exceptional processing power, it can handle most arduous tasks too. The stylus makes it a good choice for designers.
A few reviews have suggested that the Surface Pro's battery life is short, while the standard gripe about the lack of Microsoft apps compared to iOS and Android remains too. However, it's pretty much the best tablet available for professionals using a tablet as their main device. If you've got the cash, give it a try (sell electronics if needs be!).
The iPad Air 2 is the nearest competitor, although it's not as 'work focused' as the Surface Pro 3. Rumours suggest that Apple will release a 'Pro' version of the iPad very soon though; it'll include a 12" display and split screen multitasking functionality.
While tablet gaming is mostly associated with 'casual' titles like Clash of Clans and Boom Beach, there is a growing demand for high-powered devices capable of console-like experiences.
At the moment, the Nvidia Shield is the best gaming-focused tablet. Available from around £240, it features an 8" screen and a Tegra K1 chip, which is one of the best processors around. Games are available from Android's Play Store, or you can stream directly from your PC. For an extra £50, you can get a dedicated controller too.
Again, we have to recommend the iPad Air 2 as well – if only for iOS' great selection of games. The Air's powerful processor and hi-res screen make it the best iOS gaming device.
This is a difficult category to choose just one tablet for, as most devices play movies in an acceptable fashion.
If you're serious about getting the best possible viewing experience, though, the Samsung Galaxy Tab S is a solid choice. It has an incredible 8.4" (or 10.5"!) AMOLED screen, which makes any film look fantastic. It only has 16GB of storage, although this can be increased with a MicroSD card.
Of course, Samsung devices tend to divide opinion. If you're not a fan of Samsung, give the Sony Xperia Z3 a try.
Nestled amongst some of the biggest names in tech, Tesco have forged quite a reputation for quality tablets at exceptional prices. The Hudl 2 isn't world-changing but it has an 8.3" HD screen, loads of apps and is pretty much perfect for kids.
The Google Nexus 7 is a good budget-friendly choice too, although it's a few years old now.
What's your favourite tablet? Let us know in the comments!
And if you want to sell your tablet, just click the button below to get started!
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How to Update Radeon Drivers Bring up your A game
If you're looking to make sure you can play the next upcoming game or want the next new features then updating your drivers is a good idea. It makes sure you're hardware is performing as well as it should or you have the latest benefits on the software side. Such as if you want to get better upscaling or ray tracing in games and make sure they perform well. 3) Click the Update button next to the flagged graphics card device to automatically download the correct version of the driver . You can update your AMD video driver to the latest version to fix any graphics issues, and bring you the best possible experience, especially when playing PC games. Optimal updates are released between recommended ones, and most often, they are at least partially, rolled into recommended versions.
It can scan out the outdated drivers in one click and allow you to update all drivers at once. With multiple versions of drivers available on the program, you can choose the best one for your device. And with its backup and restore feature, you can back up the driver files for further uses. The dedicated built-in utility is responsible for keeping most of your devices' drivers up-to-date silently. DriverPack is a completely free driver updater tool that is best for novice users as it can automatically handle all driver updating needs without user interference. You just need to click on the Start installing button, and it will automatically scan and updated all drivers.
Updating Drivers
That's one of the reasons, in fact, that people don't know that much about drivers. In general, you don't need to fuss about whether or not to update your drivers. While there are some drivers that Windows doesn't automatically update, they're by and large covered. CPU drivers updating is crucial for confirming that your system's hardware is compatible with the latest Windows updates. CPU driver update also fixes bugs and errors with the previous CPU driver.
Once it detects that, the tool will show you the list of all the updated drivers that are compatible with your system which you can easily install.
Right-click the name of your graphics card or display adapter, then select Update Driver.
A window will appear asking how you want to search for available drivers.
You should visit the website of the notebook manufacturer to download the latest driver. If you are prompted to restart your computer after the installation is complete, do so. There's also another reason to keep some drivers up to date, and that's due to security issues. In this guide, we'll show you how to update Intel, AMD and Nvidia drivers in Windows 10 manually. Outdated Windows 10 drivers may cause sluggish performance and stability issues with peripherals after applying certain Windows Updates. Updating drivers could also improve the overall performance of the system, address Wi-Fi connectivity issues and stabilize Bluetooth connections.
How to set up an AMD Radeon graphics card and select the right drivers for it in Zorin OS. To find your new graphics driver, head to the Nvidia driver page. There make sure to put download here in your graphics card to find the newest driver. It is quite easy to the updated driver to the latest version but in some cases, you would find it difficult for AMD graphic driver. So, in such a situation follow any of the above steps and make it possible to get a new feature of the driver.
Use the Memory in the Windows Calculator
If there is a graphics driver update, it will be included in the Mac OS X update. Some possible search terms are the name of your computer manufacturer or generic terms like "update", "maintenance" or "driver". You may be required to use this tool to update graphics drivers. If you're downloading drivers to install on another device, you can copy or extract the files to a USB flash drive and connect it to the other computer.
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Hot on the heels of her record-breaking third #1 hit "Peter Pan,"Kelsea Ballerini released her new single, "Yeah Boy," to Country radio this week. Digging even deeper into debut album THE FIRST TIME (Black River Entertainment), CMT's Breakout Artist of the Year proves just how adept she is at pairing relatable lyrics with irresistible hooks: even a superstar like Taylor Swift couldn't help tweeting about "Yeah Boy" on first listen, calling it "SO lovely." With 68 first-week adds, Ballerini looks primed to prove yet again why her voice has found a home in the heart of country fans worldwide.
The Black River recording artist recently celebrated her 23rd birthday by topping both Country Aircheck andBillboard Country Airplay charts with "Peter Pan," which also earned double #1's on Billboard, making Ballerini the first woman to reach #1 on Billboard's Hot Country Songs and Country Airplay charts simultaneously.
To cap off this outstanding year, Ballerini will receive CMT's second-annual Breakout Artist of the Year award during the network's "2016 Artists of the Year" special, premiering October 20 at 8 p.m. ET/PT, and November 2 will find her at the 50th annual CMA Awards, where she is nominated in two categories: New Artist of the Year and Female Vocalist of the Year. She is also vying for Favorite Female Artist – Country atthe fan-voted American Music Awards on Sunday, November 20, airing live at 8|7 p.m. CT on ABC. Voting is now open through November 14 at amavote.com.
Ballerini holds the distinction of having written all three GOLD-certified songs from her debut album THE FIRST TIME, including her PLATINUM-certified debut single, "Love Me Like You Mean It." Produced by Forest Glen Whitehead and Jason Massey, THE FIRST TIME showcases Ballerini's skillful songwriting on each of the 12 songs. After spending the summer winning over audiences on Rascal Flatts' RHYTHM & ROOTS Tour, Ballerini is set to headline her own tour, aptly titled, THE FIRST TIME Tour. Kicking off this fall, she is already proving her crowd-drawing potential with two shows confirmed as early sell-outs, including her hometown concert in Knoxville (11/11) and Minneapolis show (11/19).


No-one who sees them together can miss it. Of all of the lovers in the history of human love, Donald and Melania are unique. Their love, a verdant field of spring flowers in bloom. Their love, as warm and radiant as the summer sky. Their love, the glory of the woods in autumn, the soft silence of a winter snowfall. Their love, so perfect the angels weep for joy in heaven.
To see them together makes the knees buckle at the sheer intensity of their passion, of the unfathomable depth of their caring, two souls, intertwined as one, destined for one another from the dawn of time.
Romeo and Juliet? Wesley and Buttercup? Gomez and Morticia? Hah. They are but flickering, faint, battery-powered tea candles against the glorious golden sun of Donald and Melania's love.
What mother does not hold her infant son in her arms and whisper, one day, my child, I want you to be loved as Donald is loved? What father does not see his daughter blossoming into her womanhood and not say, oh, my child, one day you shall find your Donald?
How could such a perfect thing be, America asks, as we together swoon at the sight of their touch? How could their divine paragon of storybook romantic bliss have ever taken shape in a cruel and heartless world?
There's a cover story, of course. We've all heard it. But I now know the true-truth, the real-truth, the secret story of their love that Kellyann Conway may or may not have whispered to me as she mistakenly drunk-skyped me at two-thirty in the morning last Thursday. This happens all the time in DC lately.
I found it hard to believe, at first, but it was Kellyann, so I know it must be true.
There's a runaway bestseller in this, I'm sure of it, and if we can get to market with it quick, it'll blow the doors off the Valentine's Day book-gift market in 2018.
I've enclosed the standard format book proposal. We'll talk soon!
It begins, of course, with a gypsy curse.
The year is 1945. Fred, a wealthy New York real estate developer, is tearing down a tenement in Queens to make room for new apartments. As he evicts the tenants, one of them...an old gypsy woman...hisses these words at him as she is dragged away: "Till he ze hand of True Love Takes, He vill... sometink... sometink....makes. Ach, the hell with rhyming! He vill haff TINY Hands! Tiny Haaaaaaands!"
Those words haunt his nightmares, nightmares that come true when his otherwise perfect firstborn son Donald is born with impossibly small hands. GI Joe Action figure hands, and not them man-doll 70's action figures, neither. Little plastic mini-figure hands. Tiny, tiny, preemie-baby-lemur hands.
The best surgeons can do nothing. Though Fred spares no expense to provide his beloved son with atomic-age clockwork prosthetics, he knows the curse can only be overcome by true love's hand in marriage.
Fred tells his son the truth of the curse on his deathbed. Suddenly aware of the truth, Donald begins a lifelong quest to find true love. Donald--now a charming, debonair man of international adventure with perfect hair--travels the globe with his nuclear steampunk cyborg hands, driven always by his father's dying wish to reverse the curse.
Donald samples all the women the world has to offer, countless women, very very beautiful, all of course completely willing and entirely receptive to his advances. But none of them, not one, are his true love. It's a mighty struggle, just as hard as fighting a ground war in Southeast Asia, but he forges on, a man possessed.
He marries, sure it is love, then marries again, but to no avail. Decades of earnestly seeking, yet the curse remains. Then, just when all hope seems lost, true love! But there are sinister forces at work, dark powers seeking to stop Donald from gaining the big love hands that could one day unite America...nay, the world...in love.
Donald and Melania is the very, very true and entirely factual story of this magical journey, a trail of hope, romance, and high adventure that leads to a love for the ages, a beacon for lovers everywhere.
Chapter 2) The Boy with Tiny Hands. So Sad!
Chapter 3) Robot Hands for Christmas. The Best!
Chapter 4) Donald Makes His Fortune With No Help.
Chapter 5) Daddy's Deathbed: The Curse Explained!
Chapter 7) Is it Ivana? The Hands? Unchanged! True love? NOPE!
Chapter 8) That Little Girl By the Side of the Road? She can't be more than SEVEN! But those EYES! Could it be HER!? IMPOSSIBLE!
Chapter 9) Is it Marla? Still Not Right. Not true love? UNACCEPTABLE!
Chapter 10) The Quest Continues: Perhaps She Is One of These Slovenian Strippers!
Chapter 11) The Little Girl! NOW ALL GROWN UP! MELANIA! Love? TRUE LOVE!
Chapter 12) The Wedding Planned! ALMOST THERE!
Chapter 13) MELANIA VANISHES! WHERE!? TERRIBLE!
Chapter 14) Melania: Prisoner of Belgian Vampire EU Bureaucrats? Bad Dudes! ONLY HE CAN SAVE HER!
Chapter 15) Donald and Bannon Put a Team Together. THE BEST!
Chapter 16) Melania Rescued! Hero!
Chapter 17) True Love! Marriage! The Curse Lifted! Hands, now the Biggest! So Big!
The author is an American who loves America. He loves a great America, an America where flags fly and the air is rich with the smell of fresh baked apple pie. He loves an America where big rear-drive cars with V8 engines ply perfect, empty roads that wind through purple mountain majesties. He loves an America where the rumble of his Harley Davidson Twin Cam 88 Dyna Glide throbs as he rides through the cool desert night in the moonlight, his fine lady pressed warm against his back.
He loves an America filled with big bright dreams and city-light striving. He loves an America filled with fresh faced country girls smiling from the beds of pickup trucks, as their strapping boyfriends hold the wheel in their calloused, honest hands. He loves an America that stands tall and proud, an America that reaches up with her big hands and touches the stars.
A full resume is available upon request.
What, are you kidding me? All of America is crying out for this book. Totally sells itself. Every American, everywhere, will buy it. Because we're all about love. True love! It's what has always made America great!