The Importance of Economic Perspective and Quantitative Approaches in Oncology Value Frameworks of Drug Selection and Shared Decision Making

The debate around value in oncology drug selection has been prominent in recent years, and several professional bodies have furthered this debate by advocating for so-called value frameworks. Herein, we provide a viewpoint on these value frameworks, emphasizing the need to consider 4 key aspects: (1) the economic underpinnings of value; (2) the importance of the perspective adopted in the valuation; (3) the importance of the difference between absolute and relative measures of risk and measuring patient preferences; and (4) the recognition of multiple quality-of-life (QoL) domains, and the aggregation and valuation of those domains, through utilities within a multicriteria decision analysis, may allow prioritization of QoL above the tallying of safety events, particularly in a value framework focusing on the individual patient. While several frameworks exist, they incorporate different attributes and—importantly—assess value from alternative perspectives, including those of patients, regulators, payers, and society. The various perspectives necessarily lead to potentially different, if not sometimes divergent, conclusions about the valuation. We show that the perspective of the valuation affects the framing of the risk/benefit question and the methodology to measure the individual patient choice, or preference, as opposed to the collective, or population, choice. We focus specifically on the American Society of Clinical Oncology (ASCO) Value Framework. We argue that its laudable intent to assist in shared clinician-patient decision making can be augmented by more formally adopting methodology underpinned by micro- and health economic concepts, as well as application of formal quantitative approaches. Our recommendations for value frameworks focusing on the individual patient, such as the ASCO Value Framework, are 3-fold: (1) ensure that stakeholders understand the importance of the adopted (economic) perspective; (2) consider using exclusively absolute measures of risk and formal patientpreference methodology; and (3) consider foregoing safety parameters for higher-order utility considerations

Nonconsumptive effects of a predator weaken then rebound over time

Predators can influence prey traits and behavior (nonconsumptive effects [NCEs]), often with cascading effects for basal resources and ecosystem function. But critiques of NCE experiments suggest that their duration and design produce results that describe the potential importance of NCEs rather than their actual importance. In light of these critiques, we re-evaluated a toadfish (predator), crab (prey), and oyster (resource) NCE-mediated trophic cascade. In a 4-month field experiment, we varied toadfish cue (NCE) and crab density ( approximating variation in predator consumptive effects, CE). Toadfish initially benefitted oyster survival by causing crabs to reduce consumption. But this NCE weakened over time (possibly due to prey hunger), so that after 2 months, crab density (CE) dictated oyster survivorship, regardless of cue. However, the NCE ultimately re-emerged on reefs with a toadfish cue, increasing oyster survivorship. At no point did the effect of toadfish cue on mud crab foraging behavior alter oyster population growth or sediment organic matter on the reef, which is a measure of benthic-pelagic coupling. Instead, both decreased with increasing crab density. Thus, within a system shown to exhibit strong NCEs in short-term experiments (days) our study supported predictions from theoretical models: (a) within the generation of individual prey, the relative influence of NCEs appears to cycle over longer time periods (months); and (b) predator CEs, not NCEs, drive longer-term resource dynamics and ecosystem function. Thus, our study implies that the impacts of removing top predators via activities such as hunting and overfishing will cascade to basal resources and ecosystem properties primarily through density-mediated interactions

O govoru mržnje

European SulfoSYS-project [SysMo P–N-01-09-23] and grant [9P23000 and P25369] by the Austrian Research fund (to C.S.) and by grant [BB/K000314/1] from the Biotechnology and Biological Sciences Research Council (to M.F.W.). Funding for open access charge: Austrian Science Fund.The recently discovered clustered regularly interspaced short palindromic repeat (CRISPR)-mediated virus defense represents an adaptive immune system in many bacteria and archaea. Small CRISPR RNAs cause cleavage of complementary invading nucleic acids in conjunction with an associated protein or a protein complex. Here, we show CRISPR-mediated cleavage of mRNA from an invading virus in the hyperthermophilic archaeon Sulfolobus solfataricus. More than 40% of the targeted mRNA could be cleaved, as demonstrated by quantitative polymerase chain reaction. Cleavage of the mRNA was visualized by northern analyses and cleavage sites were mapped. In vitro, the same substrates were cleaved by the purified CRISPR-associated CMR complex from Sulfolobus solfataricus. The in vivo system was also re-programmed to knock down mRNA of a selected chromosomal gene (β-galactosidase) using an artificial miniCRISPR locus. With a single complementary spacer, ∼50% reduction of the targeted mRNA and of corresponding intracellular protein activity was achieved. Our results demonstrate in vivo cleavage of mRNA in a prokaryote mediated by small RNAs (i.e. analogous to RNA interference in eukaryotes) and the re-programming of the system to silence specific genes of interest.Publisher PDFPeer reviewe

Genetic risk for Alzheimer disease in children: Evidence from early-life IQ and brain white-matter microstructure

It remains unclear whether the genetic risk for late-onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late-onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white-matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well-validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White-matter microstructure was assessed by measuring fractional anisotropy (FA) of whi

Unconventional spin fluctuations in the hexagonal antiferromagnet YMnO3_3

We used inelastic neutron scattering to show that well below its N\'{e}el temperature, $T_{\rm N}$, the two-dimensional (2D) XY nearly-triangular antiferromagnet YMnO$_{3}$ has a prominent {\it central peak} associated with 2D antiferromagnetic fluctuations with a characteristic life time of 0.55(5) ps, coexisting with the conventional long-lived spin-waves. Existence of the two time scales suggests competition between the N\'{e}el phase favored by weak interplane interactions, and the Kosterlitz-Thouless phase intrinsic to the 2D XY spin system.Comment: 4pages, 5figure

Anomalous diffusion and the first passage time problem

We study the distribution of first passage time (FPT) in Levy type of anomalous diffusion. Using recently formulated fractional Fokker-Planck equation we obtain three results. (1) We derive an explicit expression for the FPT distribution in terms of Fox or H-functions when the diffusion has zero drift. (2) For the nonzero drift case we obtain an analytical expression for the Laplace transform of the FPT distribution. (3) We express the FPT distribution in terms of a power series for the case of two absorbing barriers. The known results for ordinary diffusion (Brownian motion) are obtained as special cases of our more general results.Comment: 25 pages, 4 figure

The composition of Singaporean shopping centres

With its growing population but limited supply of land, Singapore has seen a huge increase in the number and size of shopping centres in recent years. This growth has led to two rather contradictory outcomes - more choice for retailers in their efforts to reach customers but also claims that too many of the centres contain the same types of retailers and contain no real differentiation in their offerings. This paper looks at this trend and reports on a survey of the composition of store types in a wide range of Singaporean shopping centres to consider whether or not these views are based on a full picture of the roles played by these shopping centres