Early Cost-Effectiveness of Onasemnogene Abeparvovec-xioi (Zolgensma) and Nusinersen (Spinraza) Treatment for Spinal Muscular Atrophy I in The Netherlands With Relapse Scenarios.

OBJECTIVES: Onasemnogene Abeparvovec-xioi (AVXS-101) is a gene therapy intended for curative treatment of spinal muscular atrophy (SMA) with an expected price of around €2 000 000. The goal of this study is to perform a cost-effectiveness analysis of treatment of SMA I patients with AVXS-101 in The Netherlands including relapse scenarios. METHODS: An individual-based state-transition model was used to model treatment effect and survival of SMA I patients treated with AVXS-101, nusinersen and best supportive care (BSC). The model included five health states: three health states according to SMA types, one for permanent ventilation and one for death. Deterministic and probabilistic sensitivity analyses were performed. Effects of relapsing to lower health states in the years following treatment was explored. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) for AVXS-101 versus BSC is €138 875/QALY, and €53 447/QALY for AVXS-101 versus nusinersen. If patients relapse within 10 years after treatment with AVXS-101, the ICER can increase up to 6-fold, with effects diminishing thereafter. Only relapses occurring later than 50 years after treatment have a negligible effect on the ICER. To comply with Dutch willingness-to-pay reference values, the price of AVXS-101 must decrease to €680 000. CONCLUSIONS: Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.

Neural mechanisms supporting the extraction of general knowledge across episodic memories.

General knowledge acquisition entails the extraction of statistical regularities from the environment. At high levels of complexity, this may involve the extraction, and consolidation, of associative regularities across event memories. The underlying neural mechanisms would likely involve a hippocampo-neocortical dialog, as proposed previously for system-level consolidation. To test these hypotheses, we assessed possible differences in consolidation between associative memories containing cross-episodic regularities and unique associative memories. Subjects learned face-location associations, half of which responded to complex regularities regarding the combination of facial features and locations, whereas the other half did not. Importantly, regularities could only be extracted over hippocampus-encoded, associative aspects of the items. Memory was assessed both immediately after encoding and 48 h later, under fMRI acquisition. Our results suggest that processes related to system-level reorganization occur preferentially for regular associations across episodes. Moreover, the build-up of general knowledge regarding regular associations appears to involve the coordinated activity of the hippocampus and mediofrontal regions. The putative cross-talk between these two regions might support a mechanism for regularity extraction. These findings suggest that the consolidation of cross-episodic regularities may be a key mechanism underlying general knowledge acquisition.

Generalization from episodic memories across time: a route for semantic knowledge acquisition.

The storage of input regularities, at all levels of processing complexity, is a fundamental property of the nervous system. At high levels of complexity, this may involve the extraction of associative regularities between higher order entities such as objects, concepts and environments across events that are separated in space and time. We propose that such a mechanism provides an important route towards the formation of higher order semantic knowledge. The present study assessed whether subjects were able to extract complex regularities from multiple associative memories and whether they could generalize this regularity knowledge to new items. We used a memory task in which subjects were required to learn face-location associations, but in which certain facial features were predictive of locations. We assessed generalization, as well as memory for arbitrary stimulus components, over a 4-h post-encoding consolidation period containing wakefulness or sleep. We also assessed the stability of regularity knowledge across a period of several weeks thereafter. We found that subjects were able to detect the regularity structure and use it in a generalization task. Interestingly, the performance on this task increased across the 4hr post-learning period. However, no differential effects of cerebral sleep and wake states during this interval were observed. Furthermore, it was found that regularity extraction hampered the storage of arbitrary facial features, resulting in an impoverished memory trace. Finally, across a period of several weeks, memory for the regularity structure appeared very robust whereas memory for arbitrary associations showed steep forgetting. The current findings improve our understanding of how regularities across memories impact memory (trans)formation.

Time, not sleep, unbinds contexts from item memory.

Contextual cues are known to benefit memory retrieval, but whether and how sleep affects this context effect remains unresolved. We manipulated contextual congruence during memory retrieval in human volunteers across 12 h and 24 h intervals beginning with either sleep or wakefulness. Our data suggest that whereas contextual cues lose their potency with time, sleep does not modulate this process. Furthermore, our results are consistent with the idea that sleep's beneficial effect on memory retention depends on the amount of waking time that has passed between encoding and sleep onset. The findings are discussed in the framework of competitive consolidation theory.