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Italian teenager Jannik Sinner upset 11th seed David Goffin in a breezy 7-5, 6-0, 6-3 victory on his French Open debut.
As Osaka walked off with a third Grand Slam title, Azarenka was denied a US Open crown for a third time having also finished runner-up in 2012 and 2013.
Pliskova's exit marked the worst performance by a women's top seed in New York since Simona Halep's opening round defeat in 2018.
The 22-year-old wore a mask honouring McClain, the 23-year-old Black man who died after a violent encounter with Aurora, Colorado, police officers in 2019, during her second round match.
Osaka's injury meant Belarusian Azarenka won her first title since 2016.
Meanwhile, world No. 1 Novak Djokovic headlines the initial men's singles entry list for the US Open, the organisers have announced.
The two-time Grand Slam champion had previously said she would withdraw from the match to protest against racial injustice.
Federer will not be at Flushing Meadows this year after he took the year off to recover from a knee surgery while defending champion Rafael Nadal joined a number of top seeds in refusing to travel to the US due to COVID-19 concerns.
Romanian Halep joined world No. 1 Ash Barty, defending champion Bianca Andreescu, Elina Svitolina, Kiki Bertens and Belinda Bencic in skipping the event at Flushing Meadows due to COVID-19 concerns.
Women's world No. 1 Ashleigh Barty, Svetlana Kuznetsova, Elina Svitolina and Kiki Bertens have already decided against playing in the US Open amid the COVID-19 pandemic.
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