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Real Madrid suffered a 2-1 LaLiga defeat at Athletic Bilbao as Kylian Mbappe missed from the penalty spot again.
Alex Berenguer prodded the hosts ahead after 53 minutes before Mbappe – who failed to convert a Champions League penalty against Liverpool last week – sent his kick too close to Bilbao goalkeeper Julen Agirrezabala.
Jude Bellingham appeared to have rescued a point for Real after scoring for the fourth successive league game 12 minutes from time.
But Federico Valverde’s mistake two minutes later gifted Gorka Guruzeta the winner in front of a delirious San Mames crowd.
On a busy night of second-round Copa del Rey action, Villarreal suffered a shock 1-0 defeat at Pontevedra while there were wins for Real Betis, Rayo Vallecano and Valencia.
Fiorentina went out of the Coppa Italia to Empoli on penalties on an emotional night at Stadio Artemio Franchi.
Viola were back in action after Edoardo Bove’s health scare forced their weekend league fixture with Inter Milan to be abandoned during the first half.
Midfielder Bove collapsed on the pitch and required emergency medical treatment. He was taken to hospital but regained consciousness in intensive care.
Empoli led at half-time through Emmanuel Ekong’s fourth-minute opener before Moise Kean and Riccardo Sottil put Fiorentina ahead.
Sebastiano Esposito struck 15 minutes from time to make it 2-2 and take the last-16 tie into extra time, Empoli eventually winning 4-3 on penalties.
Benjamin Sesko opened the scoring and Luis Openda struck twice as RB Leipzig brushed aside Eintracht Frankfurt 3-0 in the German DFB Pokal.
Second-half goals from Denis Vavro, Jonas Wind and Yannick Gerhardt saw Wolfsburg beat Hoffenheim 3-0.
Cologne knocked out Hertha Berlin 2-1 after extra time with Dejan Ljubicic converting a penalty in the final seconds, while Augsburg prevailed 5-4 on penalties against Karlsruhe after a 2-2 draw.
