French Open champion Garbine Muguruza and Wimbledon finalist Milos Raonic made shock exits in the second round of the US Open.
Canada’s Raonic, the fifth seed, struggled physically as American qualifier Ryan Harrison – the world number 120 – won 6-7 (4-7) 7-5 7-5 6-1.
Spanish third seed Muguruza lost 7-5 6-4 to Latvia’s Anastasija Sevastova.
Top seed Novak Djokovic reached round three without hitting a ball as Jiri Vesely withdrew before their match.
The Czech, 23, said he was “very, very disappointed” to pull out with inflammation of his left forearm.
Defending champion Djokovic, who has been struggling with a wrist injury, gets three days off before facing Russia’s Mikhail Youzhny on Friday.
Former champion Marin Cilic and French seeds Gael Monfils and Jo-Wilfried Tsonga progressed, with fourth seed Rafael Nadal to play Italy’s Andreas Seppi later on Wednesday.
Cramp ends Raonic hopes
Raonic was among the favorites for the title after reaching the semi-finals at the Australian Open and the final at Wimbledon, losing to Andy Murray on both occasions.
However, the 25-year-old struggled to carry his bags by the time he left the court following defeat by Harrison.
“It was probably just nerves and stress, a mental sort of over-exuberance,” Raonic said.
“Cramping in the left arm, right forearm there towards the end of the third set, both quads, a little bit in the hip flexor on the left. It was just catching me all over.
“I couldn’t switch grips from one point to the next. There were a few points where I would hold the racquet with my left hand and trying to stretch out my right hand in between shots, and that’s not going to work.”
‘Shaking’ Sevastova conquers nerves
Muguruza, making her debut on the Arthur Ashe Stadium, got the first break of serve before being overhauled by Sevastova, ranked 48th in the world.
The Spaniard, 22, fought back from facing two match points at 5-1 down in the second set to get back on serve at 5-4, only for Sevastova to claim a seventh break of the night.
“I had to solve my head, myself, what could be, what could not,” Sevastova said of the battle with her nerves in the closing stages.
The Latvian, who retired in 2013 because of injuries and illness before returning in 2015, added: “I was shaking a little bit in the end but it’s amazing.
“A night match on Ashe – what’s going to be bigger?”
I belong at the top – Wozniacki
Two-time finalist Caroline Wozniacki fought back superbly to beat ninth seed and former champion Svetlana Kuznetsova.
Wozniacki, a former world number one, has slipped to 74th in the rankings and was one point from falling behind 5-0 against Kuznetsova.
However, the Dane battled back to win 6-4 6-4 and reach the third round at a Grand Slam for the first time since Wimbledon last year.
“I stopped looking at the ranking once I fell out of the top 10,” the 26-year-old said. “I feel like I belong at the top.
“Today I beat someone who’s been playing really well this year and that’s definitely going to build my confidence.”
Germany’s Angelique Kerber, seeded second and in with a chance of taking the number one ranking, beat Mirjana Lucic-Baroni of Croatia 6-2 7-6 (9-7).
Kerber will next face 17-year-old qualifier Cici Bellis, who beat fellow American Shelby Rogers 2-6 6-2 6-2.
Roberta Vinci, Dominika Cibulkova, Johanna Konta and Petra Kvitova were other seeds to progress.
Britons through in doubles
Fourth seeds Jamie Murray and Brazilian Bruno Soares came through a tight opening match against Gastao Elias and Joao Sousa, seeing off the Portuguese pair 6-3 6-7 (3-7) 7-5.
They were joined in the last 32 by the pairing of Britain’s Dan Evans and Australian Nick Kyrgios, who defeated Americans Daniel Nguyen and Noah Rubin 6-3 6-3.