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Middlesex 142 for 2 (Stoneman 80*) trail Leicestershire 149 (Helm 3-23, Shaheen 3-54) by seven runs
The Seaxes, who dismissed Glamorgan cheaply twice to secure an innings victory last week, bowled their visitors out for 149, with Afridi repeating his debut feat from Cardiff by striking twice in as many balls to wreck the Foxes' top order.
The Pakistan paceman finished with figures of 3 for 54, while Helm bettered that return with 3 for 23.
Mark Stoneman cemented Middlesex's advantage with an unbeaten 80 to steer his side to 142 for 2 at the close, a deficit of only seven.
With cloud overhead, it was little surprise when home skipper Peter Handscomb opted to bowl after winning the toss - and his bowlers quickly proved the wisdom of that decision by reducing Leicestershire to 55 for 6 before lunch.
Afridi captured the first three wickets as Hassan Azad nudged low to first slip and Colin Ackermann, hanging the bat out, dragged his first delivery onto the stumps before Louis Kimber was bowled by a ball that nipped back.
Toby Roland-Jones - having beaten the bat several times without reward - switched ends and prised out the stubborn Sam Evans, caught behind after lasting an hour and a half for only nine runs.
Helm also bowled with pace and venom from the Nursery End, collecting wickets either side of the interval and alternating with Ethan Bamber (2-23), whose steady line accounted for Harry Swindells before Chris Wright was clean bowled.
However, last man Beuran Hendricks (22) played some productive shots, surviving a sharp slip chance off Luke Hollman and clubbing both the leg-spinner and Afridi to the fence as he and Callum Parkinson (25 not out) built a partnership of 39.
That stand, the highest of the innings, eventually ended when Hendricks was bowled swinging at Hollman and missing, but it had at least given the Foxes some impetus going into the field.
Wright immediately found the edge of Sam Robson's bat and, although the ball dropped narrowly short of third slip, he and Hendricks initially kept Middlesex's opening pair under a tight rein.
Stoneman threw off the shackles in the 10th over, doubling the total with a succession of boundaries off Hendricks and strode towards his half-century, dispatching Wiaan Mulder for four more through the covers to reach the landmark.
Ed Barnes made the breakthrough, pinning Robson (16) leg before - and Leicestershire might also have removed Robbie White without scoring, Ackermann shelling a chance off Wright at second slip.
Having taken 40 minutes to get off the mark, White advanced to 23 before Mulder had him caught in the slips off the final ball of the day.
Middlesex chase down easy target for 10-wicket win over Leicestershire
Ben Mike stranded on 99 as thrilling counter-attack fails to save visitors
Mark Stoneman ton puts Middlesex ahead before Shaheen Shah Afridi inflicts more pain
John Simpson, Luke Hollman put on century stand to suck life out of Leicestershire hopes after Stoneman falls