We aimed to determine whether uncertainties identified by the European Medicines Agency (EMA) were associated with negative relative effectiveness assessments (REA) and negative overall reimbursement recommendations by national health technology assessment (HTA) agencies. Therefore, we identified all HTA reports from HAS (France), NICE (England), SMC (Scotland) and ZIN (the Netherlands) for a cohort of innovative medicines that EMA had approved in 2009-2010 (excluding vaccines). Uncertainty regarding pivotal trial methodology, clinical outcomes and their clinical relevance were combined to reflect a low, medium or high level of uncertainty. We assessed associations by calculating risk ratios (RR) and 95% confidence intervals (CI), and agreement between REA and overall reimbursement recommendation outcomes. We identified 36 medicines for which 121 reimbursement recommendations had been issued by the HTA agencies between September 2009 and July 2018. High vs. low uncertainty was associated with an increased risk for negative REAs and negative overall reimbursement recommendations: RRs 1.9 (95% CI 0.9-3.9) and 1.6 (95% CI 0.7-3.5), respectively, which was supported by further sensitivity analyses. We identified a lack of agreement between 33 (27%) REA and overall reimbursement recommendation outcomes, which were mostly restricted recommendations that followed on negative REAs in case of low or medium uncertainty. In conclusion, high uncertainty identified by EMA was negatively associated with REAs and overall reimbursement recommendations. To reduce uncertainty and ultimately facilitate efficient patient access, regulators, HTA agencies and other stakeholders should discuss how uncertainties should be weighed and addressed early in the drug life cycle of innovative treatments.
In the absence of light signals, Arabidopsis plants fail to develop the rosette habit typical for this species. Instead, plants display caulescent growth due to elongation of rosette internodes. This aspect of photomorphogenic development has been paid little attention and molecular events involved, downstream of photoreceptor signaling, remain to be identified.Using a combination of genetic and molecular approaches, we show that Arabidopsis rosette habit is a photomorphogenic trait controlled by induction of ARABIDOPSIS THALI-ANA HOMEOBOX GENE1 (ATH1) as downstream target of multiple photoreceptors.ATH1 induction prevents rosette internode elongation by maintaining the shoot apical meristem (SAM) rib zone area inactive and requires inactivation of photomorphogenesis inhibitors, including PHYTOCHROME INTERACTING FACTOR (PIF) proteins. ATH1 activity results in tissue-specific inhibition of PIF expression, establishing double-negative feedbackregulation at the SAM. Light-requirement for ATH1 expression can be overcome by high sugar availability to the SAM. Both sugar and light signals that induce ATH1 and, subsequently, rosette habit are mediated by TOR kinase.Collectively, our data reveal a SAM-specific, double-negative ATH1-PIF feedback loop at the basis of rosette habit. Upstream, TOR kinase functions as central hub integrating light and energy signals that control this for Arabidopsis quintessential trait.
Here, we demonstrate that Arabidopsis rosette habit is a bona fide photomorphogenic trait controlled by the homeodomain protein ATH1. In light, ATH1 expression at the SAM is induced by broad wavelengths, mediated through multiple photoreceptors, and requires inactivation of COP1 and PIF photomorphogenesis inhibitors. Such induced ATH1 prevents elongation of rosette internodes by maintaining the rib zone area of the SAM in an inactive state. In the absence of light, Arabidopsis plants cannot complete seedling establishment after germination due to inactivity of the shoot apical meristem (SAM). Light requirement for SAM activation can be overcome by availability to the meristem of metabolizable sugars, such as sucrose. However, under these conditions plants fail to establish a typical compact rosette and display a caulescent growth habit. We show that this is due to insufficient expression of ATH1 at the SAM. ATH1 induction restores rosette habit in dark-grown plants through inhibition of PIF gene expression. Together, this suggests that a SAM-specific, double-negative ATH1-PIF feedback loop is at the basis of Arabidopsis rosette habit. Induction of ATH1 expression and restoration of rosette habit in darkness also occurs at increased levels of sucrose. Both sugar and light signals that induce ATH1 are mediated by TOR kinase. Overall, these results support a fundamental role for ATH1 in Arabidopsis rosette habit and further strengthen a role for TOR kinase as a central hub for integration of energy and light signals controlling organogenesis at the SAM.
Bariatric surgery is a common applied surgical intervention in individuals with obesity to achieve weight-loss, to reduce comorbidities and improve overall survival. However, commonly performed techniques are associated with physiological changes in the gastrointestinal tract that may lead to changes in oral drug disposition. Furthermore, recommended dietary restrictions after bariatric surgery might influence drug disposition and due to prophylactic prescribed drugs interactions might occur. Also, in the years after bariatric surgery, patients will lose weight. These alterations can influence oral drug disposition of oral antineoplastic drugs and, subsequently influence outcomes of breast cancer treatment. The purpose of this review is to provide an overview of the available evidence on the effect of bariatric surgery on the pharmacokinetics of oral antineoplastic drug used in breast cancer treatment. We performed a comprehensive analysis of published pharmacokinetic and pharmacodynamics data. Subsequently we provide, where possible, recommendations on preferences within therapeutic classes and provide recommendations when prescribing oral antineoplastic drugs for breast cancer. Due to the limited availability of clinical evidence on oral drug disposition and subsequently outcomes in this population, our advice is to monitor patients extensively for efficacy but also for safety before and after surgery.
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