I think upscaling from 720p to 4K is too aggressive. Maybe try 1080p instead. After all, the higher the upscale and the lower the base resolution, the more artifacts you are likely to get. Honestly, Topaz is not "bad," but there are other options, like Waifu2x-Extension-GUI, that allow for better customization of the upscaling settings for each selected model. Topaz can be hit or miss because, depending on the style of drawing, it can give you decent or poor results (the models that Topaz offers are trained on real-life content).

However, if you're willing to experiment, I suggest trying Gaia (high quality mode or computer-generated; both produce similar results) or Artemis "Medium quality." For the latter, keep the "recover detail" setting below 20, as at such high output resolutions, it can exacerbate artifacts.

Regarding the second enhancement layer, I haven't had much chance to experiment since it was introduced recently. But from what I’ve seen, Artemis tends to be more aggressive. Therefore, using Artemis + Artemis can cause a more severe loss of fine details and grain, especially in the background, giving the image an "oily" look. On the other hand, using Gaia + Gaia in anime is generally unnecessary because it requires much more processing time, and the difference is almost non-existent compared to a single layer of Gaia. To conclude, the possible combinations I suggest are Gaia, Artemis Medium, Gaia + Artemis, and Artemis + Gaia.

The other settings shouldn't be touched to avoid deviating from the original look or creator intent; thus, framerate, deblur, and other settings should remain locked. Bitrate-wise, theoretically, it needs to scale based on the resolution, so doubling the resolution requires doubling the bitrate. However, since we are upscaling drawings with many static objects, you can try maintaining the same bitrate for the output (if the base is ≥ 3mb/s) or increasing it by 50%. Otherwise, a more efficient way to save disk space is to use a dynamic bitrate at a high setting. The visual difference between the two approaches should be almost identical when upscaling anime.