I'm a recent S2721DGF owner as well and initially had some eyestrain with it. I've had mine for about 2 weeks now. I'm currently on Windows 7, and plan to build a new PC sometime early this year once parts become more available and prices return to normal. The plan is to dual boot Linux and Windows 10, and use Linux as my daily OS and Windows 10 for gaming.
Last year I spent a lot of time on Linux, but got terrible eyestrain which I believe was something wrong between my current GPU and Linux (and or the GPU driver). I eventually gave up on Linux until I build the new system, but I recently hopped back into Linux to see if any of the new kernels or GPU drivers have changed anything. I did notice they fixed the Nvidia X Server Settings issue I was having where it kept re-enabling dithering. I was still getting some eyestrain, but when I disabled dithering and forced the color dynamic range from Full to Limited, it became quite usable, but the choppy scrolling in browsers, and when moving windows around still told me Nvidia is still a pile of junk on Linux. Anyway, I'm digressing from the topic of this S2721DGF monitor.
Before I got the monitor I did notice a few comments on the monitors subreddit about people have eyestrain with the S2721DGF and most believed it to be the Nano IPS technology where the red phosphors are very strong on the eye. I did notice the red colors out of the box were much stronger than my older IPS. I didn't spend more than 10 minutes though with the out of the box settings. I threw my i1 Display Pro colorimeter on the display and calibrated it. This dialed back the strong over-saturated reds and the color now looked a lot closer to my old IPS that I had calibrated as well.
However, it wasn't the color that was the problem for me, it was going from 1080p to 1440p that was the issue. The new resolution changed all the fonts size and my eyes were having a hard time trying to focus on the text. I tried changing the DPI to 125% and this made all the fonts very similar in size to my 1080P monitor, but on Windows 7 the DPI scaling is a bit wonky and it's much better in Windows 10. I eventually settled on keeping the scaling to 100% and instead changed some font sizes in the "Windows Color and Appearance" dialog to make them bigger in titlebars and Windows Explorer folders. In Firefox, it's simply a matter of changing the about:config setting layout.css.devPixelsPerPx to 1.25 to get the same scaling effect. With these changes, it made the scaling on most things similar to what 1080p looks like, but it did keep my taskbar fonts and windows dialog fonts the native 1440p 100% size. I wanted to try and force myself to get used to the native resolution size of some things in case I wanted to actually utilize the point of going to 1440p for the increased workspace.
The focusing issue was only minor compared to the terrible eyestrain I got when using Linux, and after about 4 or 5 days my eyes adjusted to the new monitor perfectly and I'm completely comfortable using it now. It felt analogous to when you get a new prescription of glasses and you feel kind of dizzy and have trouble focusing on things for the first few days. I do have Astigmatism in both my eyes as well like you, but I don't recall the exact numbers.
For reference, my current system is:
MSI GTX 970 SLI
Dell S2721DGF 27" 165hz 1440p IPS via DisplayPort (primary monitor)
LG 27MP89HM-S 27" 60hz 1080p IPS via HDMI (secondary monitor; was primary before)
Both monitors are calibrated to 120cd/m2 / 6500K / 2.2 Gamma. Prior to calibration in DisplayCal on the S2721DGF, my brightness setting to reach 120 cd/m is 37%, and I used the the Custom RGB Gain of R = 95%, G = 94%, B = 100%. The rest of the monitor settings are stock.
I do have one worry though about when I move to the new system. It seems the GTX 970 can only output 8bpc (at least, that's all it allows in the Nvidia Control Panel), and the S2721DGF can apparently be set to 10bpc on newer GPUs. However, the monitor is actually 8bit + FRC. My worry is that because I'm currently outputting at 8bpc, the FRC part of the monitor might be disabled, and when I move to the new system and set it to 10bit, Frame Rate Control would be enabled and might be the cause of some eyestrain. Not sure if that's how FRC actually works though. I suppose if it does cause eyestrain, I could always just back it down to 8bpc again.
My suggestion to you was to try and set your color output to 8bpc instead of 10bpc, but I see you are also on a GTX 970, so you're probably stuck with 8bpc like myself. You could try changing the output dynamic range from Full to Limited in the Nvidia Control Panel; this helped for me in Linux. You could try using an HDMI cable instead of the DP cable to see if that helps any. You will be limited to 144hz instead of 165hz though.
Rtings review of the monitor did report an odd 20KHz flicker with their review sample, so maybe some of these units have flickering issues at other frequencies that might be causing your eyestrain. This might have been fixed though in newer units. What manufacturer month is your S2721DGF? It's on the sticker on the back of the monitor. Mine says Nov 2020. Rtings review was done in Sept 2020, so they would have an older unit. I'm still tempted to get a Photodetector and Oscilloscope to test for these sorts of flickering/dithering problems on my own monitors, but my knowledge of analog electronics is almost nil, and I'm worried I wouldn't know how to use the hardware correctly and just end up wasting money on these devices.
Anyways, just stating my experience with my S2721DGF and hope something in it may be of help.