Analyzing labour supply of elderly people: a life-cycle approach

In light of the ageing of the Dutch society, policy measures aim at increasing the participation rate of elderly workers, particularly in the age-group between 55 and 64. This paper develops a stylized numerical simulation model. This model describes consumption, savings and labour supply behaviour over the life cycle to analyze the labour-market implications of such proposals. For example, we simulate a shift in the (normal) retirement age from 65 to 67, the elimination of the Social Security premium exemption after age 65, and a premium on first-tier pension benefits if the commencement date of these benefits is postponed. Each of these reforms affect the economic outcomes via wealth effects, income effects and inter- and intratemporal substitution effects. The stylized model offers a profound theoretical underpinning which helps us to understand these policy effects over the entire life cycle of individuals. However, the numerical outcomes should be taken with some caution as the model ignores insights of behavioural economics (such as ‘framing effects’).

Quantification of cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and its metabolite regorafenib M2 in human plasma by UPLC-MS/MS

Contains fulltext : 218233.pdf (Publisher’s version ) (Open Access)A sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of seven oral oncolytics (two PARP inhibitors, i.e. olaparib and niraparib, and five tyrosine kinase inhibitors, i.e. cobimetinib, cabozantinib, dabrafenib, vemurafenib and regorafenib, plus its active metabolite regorafenib M2) in EDTA plasma was developed and validated. Stable isotope-labelled internal standards were used for each analyte. A simple protein precipitation method was performed with acetonitrile. The LC-MS/MS system consisted of an Acquity H-Class UPLC system, coupled to a Xevo TQ-S micro tandem mass spectrometer. The compounds were separated on a Waters CORTECS UPLC C18 column (2.1 x 50 mm, 1.6 mum particle size) and eluted with a gradient elution system. The ions were detected in the multiple reaction monitoring mode. The method was validated for cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and regorafenib M2 over the ranges 6-1000, 100-5000, 10-4000, 200-2000, 200-20,000, 5000-100,000, 500-10,000 and 500-10,000 mug/L, respectively. Within-day accuracy values for all analytes ranged from 86.8 to 115.0% with a precision of <10.4%. Between-day accuracy values ranged between 89.7 and 111.9% with a between-day precision of <7.4%. The developed method was successfully used for guiding therapy with therapeutic drug monitoring in cancer patients and clinical research programs in our laboratory

Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer

Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C min at steady-state. The geometric mean (GM) C min at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C min at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P <.001) for SGC and RCC patients, respectively. When dose-normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (C min 971 μg/L [95% CI: 790-1193] vs 669 μg/L [95% CI: 568-788]) (P =.005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM C min at BTD were comparable between the SGC and the RCC group, 694 μg/L (95% CI: 584-824) vs 583 μg/L (95% CI: 496-671) (P =.1). The observed cabozantinib exposure at BTD of approximately 600 μg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity

Dose recommendations for anticancer drugs in patients with renal or hepatic impairment

Renal or hepatic impairment is a common comorbidity for patients with cancer either because of the disease itself, toxicity of previous anticancer treatments, or because of other factors affecting organ function, such as increased age. Because renal and hepatic function are among the main determinants of drug exposure, the pharmacokinetic profile might be altered for patients with cancer who have renal or hepatic impairment, necessitating dose adjustments. Most anticancer drugs are dosed near their maximum tolerated dose and are characterised by a narrow therapeutic index. Consequently, selecting an adequate dose for patients who have either hepatic or renal impairment, or both, is challenging and definitive recommendations on dose adjustments are scarce. In this Review, we discuss the effect of renal and hepatic impairment on the pharmacokinetics of anticancer drugs. To guide clinicians in selecting appropriate dose adjustments, information from available drug labels and from the published literature were combined to provide a practical set of recommendations for dose adjustments of 160 anticancer drugs for patients with hepatic and renal impairment

The impact of a 1-hour time interval between pazopanib and subsequent intake of gastric acid suppressants on pazopanib exposure

Co-treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH-dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1-hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady-state pazopanib trough concentration (C(min) ) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) C(min) levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM C(min) levels were lower in GAS users vs non-GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1-26.7] vs 28.2 mg/L [95% CI: 25.9-30.5], P = .015 and 26.0 mg/L [95% CI: 22.4-30.3] vs 33.5 mg/L [95% CI: 30.3-37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non-GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub-analysis showed lower GM pazopanib C(min) in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non-users. Our research showed that a 1-hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy

The Effect of Using Pazopanib With Food vs. Fasted on Pharmacokinetics, Patient Safety, and Preference (DIET Study)

Pazopanib is taken fasted in a fixed oral daily dose of 800 mg. We hypothesized that ingesting pazopanib with food may improve patients' comfort and reduce gastrointestinal (GI) adverse events. Therefore, we investigated the bioequivalent dose of pazopanib when taken with food compared with 800 mg pazopanib taken fasted. In addition, we investigated the differences in GI toxicity, patient satisfaction, and patient's preference for either intake. The intake of 600 mg pazopanib with food resulted in a bioequivalent exposure and was preferred over a standard pazopanib dose without food. No differences were seen in GI toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects and satisfaction with their therapy when pazopanib was taken with food. Forty-one of the patients (68%) preferred the intake with a continental breakfast

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant - a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current LAS era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N=3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤ 45 years, p<0.0001), were less often smokers (35% vs. 46%, p<0.0001), had more often clear chest X-rays (82% vs. 72%, p<0.0001), had better donor oxygenation ratio's (20% vs. 26% with PaO /FiO ≤ 300 mmHg, p<0.0001) and had better lung donor score values (LDS) (28% vs. 17% with LDS=6, p<0.0001) compared to donors used for LTx in countries with low donation rate. Survival rates for the groups LDS =6 and ≥7 at 5 years were 69.7% and 60.9% (p=0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized

Выявление понятий и их взаимосвязей в рамках технологии контент-мониторинга

Приведены подходы к решению проблемы выявления фактографической информации из неструктурированных текстовых потоков. Описаны технологические решения, позволяющие извлекать из полнотекстовых документов такие понятия как фирмы, фамилии, географические названия и т.п., а также выявлять силу их взаимосвязей на основе применения двух алгоритмов. Первый из этих алгоритмов основывается на учете совместного вхождения понятий в одни и те же документы, а второй на учете общего для рассматриваемых понятий контекста.Наведено підходи до вирішення проблеми виявлення фактографічної інформації з неструктурованих текстових потоків. Описано технологічні рішення, що дозволяють добути з повнотекстових документів такі поняття як фірми, прізвища, географічні назви тощо, а також виявляти силу їхніх взаємозв’язків на базі застосування двох алгоритмів. Перший з цих алгоритмів базується на врахуванні спільного входження понять до одних і тих самих документів, а другий — на врахуванні загального для понять, що розглядаються, контексту.Approaches to the solution of a problem of revealing factual information from unstructured text flows are given. The technological solutions, allowing to take from text-through documents such concepts as a firm, a surname, place names, etc., and also to reveal force of their interrelations on the basis of application of two algorithms are described. The first of these algorithms is based on the account of joint concepts occurrence in the same documents, and the second one on the account of the context common for considered concepts

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant – a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2/FiO2 ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized

Lung allocation score: The Eurotransplant model versus the revised US model - a cross-sectional study

Both Eurotransplant (ET) and the US use the lung allocation score (LAS) to allocate donor lungs. In 2015, the US implemented a new algorithm for calculating the score while ET has fine-tuned the original model using business rules. A comparison of both models in a contemporary patient cohort was performed. The rank positions and the correlation between both scores were calculated for all patients on the active waiting list in ET. On February 6th 2017, 581 patients were actively listed on the lung transplant waiting list. The median LAS values were 32.56 and 32.70 in ET and the US, respectively. The overall correlation coefficient between both scores was 0.71. Forty-three per cent of the patients had a < 2 point change in their LAS. US LAS was more than two points lower for 41% and more than two points higher for 16% of the patients. Median ranks and the 90th percentiles for all diagnosis groups did not differ between both scores. Implementing the 2015 US LAS model would not significantly alter the current waiting list in ET