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A few years back, in its first major refinement, drug coverage was added to the program: Part D. But it's a Rube Goldberg contraption in which private insurance companies, on behalf of the government, manage the plans.
It is a major refinement rather than an overhaul of a genre, but this universe has lost none of the magic that was there in Fallout 3 and New Vegas, which makes it so exciting to dive back into.
It shouldn't come as a surprise that the iPad looks like a major refinement in the digital distribution of entertainment and information, an area where others have taken the first imperfect steps.
The major refinement of expectations is the trade-off between adaptive speed and adaptive accuracy, as revealed by the presence of a competitor and contrary to the expectation from single-species models.
This major refinement in manipulating the murine genome utilizes the Cre recombinase from bacteriophage P1, which catalyzes the excision of an essential element of a target gene (for instance a coding exon) located between two loxP (locus of X-ing) recognition sites.
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Two major refinements that changed the research thrust were (1) the inclusion of Aleut hunters and fishers on the biological expedition itself to ensure that subsistence foods and methods were represented, and (2) the addition of a fisheries biologist on a NOAA research trawler to allow sampling of commercial fishes.
Across platforms the interface is seeing some major refinements as iMovie for Mac continues to gather more iOS visual cues.
(Baggott 2004 contains a readable account of the major refinements and experiments. Genovese 2005 is an exhaustive technical review).
Other major refinements were done: divisions were simplified in order to be power of two divisions, dataflow model was further refined to a SystemC/C++ of combined finite state-machines and data paths, loops were exploited, and timing and scheduling were taken into consideration.
Major refinements were suggested from these reviews, including modifications to the presentation format (e.g., larger font, more use of images), moving the SDM steps to the beginning of the case, and adding a module on patient decision aids with links to resource materials.
More recently, there have been major refinements to the concepts of prodromal and critical periods for early psychosis to include the more elaborated notion of clinical staging, thereby capturing a greater continuum of the journey from early symptoms to established illness 11 Further, the concept has been broadened to include young people with emerging mood disorders.
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Since I tried Ludwig back in 2017, I have been constantly using it in both editing and translation. Ever since, I suggest it to my translators at ProSciEditing.

Justyna Jupowicz-Kozak
CEO of Professional Science Editing for Scientists @ prosciediting.com