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Healthcare leaders have called on the British Medical Association (BMA) to call off the proposed series of five-day strikes by junior doctors later this month.
NHS Providers and the NHS Confederation, which represent NHS hospital, community, mental health and ambulance service trusts in England, said the planned action would lead to around 125,000 lost operations and over one million lost outpatient appointments.
Chris Hopson, chief executive of NHS Providers, said: "With barely any notice for trusts to prepare, this unprecedented level of strike action will cause major disruption and risk patient safety.
"NHS trust leaders agree with the Academy of Medical Royal Colleges that this action is disproportionate."
He added that less than 40% of junior doctors supported rejecting an agreement "strongly endorsed by their own representatives".
Theresa May has been urged to "pause" plans to bring in a new junior doctors' contract after the issue led to an extended stand-off and planned strikes.
Elizabeth McAnulty of the Patients Association told ITV News that the prime minister should suspend work on the controversial new deal - as she previously did with the Hinkley point power plant.
She called on Ms May to "step in and stop this - pause it - until she's had an opportunity to really look at the facts" as patients face repeated strikes by junior doctors over the rest of the year.
Ms McAnulty said the impact of the strikes on patients would be "devastating" and they would lead to some 30,000 operations being cancelled.
Junior doctors' planned series of strikes are an "unforgivable" betrayal of those needing care, the Patients Association has said.
Chief executive Katherine Murphy said it was a "disturbing" time to be an NHS patient as she warned medics may have gone a "step too far".
She added that the public supported the medical profession but the extent of the strikes risked eroding public trust.
A series of five-day long strikes by junior doctors could force the NHS to cancel up to half a million operations and four million appointments, a health boss has suggested.
Chris Hopson, chief executive of NHS Providers, which represents frontline NHS leaders, said the actions would cause "unprecedented" disruption to patients.
"We're talking about four sets of five days of strikes," he told BBC Breakfast.
"That's equivalent to half a million - 500,000 - cancelled operations and four million lost outpatient appointments, so what we're talking about is a completely unprecedented scale of disruption and negative impact on patients; it's extremely worrying."
Planned junior doctors' strikes throughout the rest of the year are a "devastating blow", a national patients' group has warned.
The Patients Association condemned the strike action as it said that the repeated stoppages would lead to cancelled operations and longer waits for treatment.
Chief executive Katherine Murphy called on both junior doctors and the government to return to talks in a fight over pay and conditions.
"At least one person a day calls our helpline specifically to ask for support following a cancelled or delayed hospital appointment or surgery," she said.
"This is only going to increase if the Government and BMA don't take this opportunity to resume meaningful and sincere negotiations to prevent further industrial action."
Former health minister and Lib Dem health spokesman Norman Lamb has said that the key problem in the dispute between junior doctors and the government over new contracts is down to a "chronic financial crisis" in the NHS.
"More strikes could be very damaging given that services are already under intolerable pressure," he said.
"I therefore repeat my call to the Government to agree to an urgent cross-party process aimed at achieving a new settlement for the NHS and care.
"There's no reason why we can't achieve a modern, highly effective NHS and care system but the government will have to work with others to achieve that."
The Academy of Medical Royal Colleges has said it is "disappointed" at the prospect of further industrial action each month until the end of the year.
In a statement, it said: "We are acutely aware that the NHS is under extreme pressure at the moment. Patient safety and quality of care must be the priority.
"We know there are genuine concerns about the contract and working arrangements, but we do not consider the proposed strikes are proportionate.
"Five days of strike action, particularly at such short notice, will cause real problems for patients, the service and the profession."
The British Medical Association has announced further strikes in addition to the ones in September announced on Wednesday.
The additional strike dates are October 5, 6, 7, 10, and 11, November 14-18, and December 5-9, and will take place only in England.
Theresa May has said that the deal on the table between the government and the BMA is a deal "that is safe for patients."
The Prime Minister cited "record levels of funding in the NHS" and more doctors in the NHS than in its history.
She reiterated that the BMA should put patients first, "not playing politics".
Latest ITV News reports
The medical regulator has urged junior doctors to seriously consider whether or not to take part in a new wave of strikes.
A five-day strike by junior doctors has been called in the ongoing dispute over contracts, but what does it mean for patients?