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(Number of events and incidence rates of acute arterial events in ant)Tj
9 0 0 9 220.592 733.4508 Tm
29.6744 0 Td
(i-)Tj
ET
BT
/Span <>BDC
/T1_3 1 Tf
9 0 0 9 220.592 733.4508 Tm
30.1924 0 Td
( )Tj
EMC
ET
BT
/T1_3 1 Tf
9 0 0 9 492.32 733.4508 Tm
(TNF exposed,)Tj
9 0 0 9 220.592 733.4508 Tm
35.245 0 Td
( )Tj
-35.245 -1.222 Td
(thiopurine exposed and unexposed patients matched to each)Tj
ET
0.82001 0.826 0.832 rg
/GS1 gs
216.592 718.201 76 -32.625 re
292.592 718.201 57 -32.625 re
349.592 718.201 64 -32.625 re
413.592 718.201 64 -32.625 re
477.592 718.201 75.684 -32.625 re
f
1 0 0 1 216.5171 718.2008 cm
/GS2 gs
0 0 m
76.075 0 l
S
1 0 0 1 0.15 -32.625 cm
0 0 m
75.925 0 l
S
1 0 0 1 75.9249 32.625 cm
0 0 m
57 0 l
S
1 0 0 1 0 -32.625 cm
0 0 m
57 0 l
S
1 0 0 1 57 32.625 cm
0 0 m
64 0 l
S
1 0 0 1 0 -32.625 cm
0 0 m
64 0 l
S
1 0 0 1 64 32.625 cm
0 0 m
64 0 l
S
1 0 0 1 0 -32.625 cm
0 0 m
64 0 l
S
1 0 0 1 64.0001 32.625 cm
0 0 m
75.759 0 l
S
1 0 0 1 0 -32.625 cm
0 0 m
75.609 0 l
S
1 0 0 1 -260.925 -13.75 cm
0.737 0.744 0.75301 RG
0.25 w
/GS3 gs
0 0 m
75.925 0 l
S
1 0 0 1 75.9249 0 cm
0 0 m
57 0 l
S
1 0 0 1 57 0 cm
0 0 m
64 0 l
S
1 0 0 1 64 0 cm
0 0 m
64 0 l
S
1 0 0 1 64.0001 0 cm
0 0 m
75.609 0 l
S
1 0 0 1 -260.925 -11.625 cm
0 0 m
75.925 0 l
S
1 0 0 1 75.9249 0 cm
0 0 m
57 0 l
S
1 0 0 1 57 0 cm
0 0 m
64 0 l
S
1 0 0 1 64 0 cm
0 0 m
64 0 l
S
1 0 0 1 64.0001 0 cm
0 0 m
75.609 0 l
S
1 0 0 1 -260.925 -11.625 cm
0 0 m
75.925 0 l
S
1 0 0 1 75.9249 0 cm
0 0 m
57 0 l
S
1 0 0 1 57 0 cm
0 0 m
64 0 l
S
1 0 0 1 64 0 cm
0 0 m
64 0 l
S
1 0 0 1 64.0001 0 cm
0 0 m
75.609 0 l
S
1 0 0 1 -260.925 -11.625 cm
0 0 m
75.925 0 l
S
1 0 0 1 75.9249 0 cm
0 0 m
57 0 l
S
1 0 0 1 57 0 cm
0 0 m
64 0 l
S
1 0 0 1 64 0 cm
0 0 m
64 0 l
S
1 0 0 1 64.0001 0 cm
0 0 m
75.609 0 l
S
1 0 0 1 -261.075 -42.125 cm
0 0 m
76.075 0 l
S
1 0 0 1 76.0749 0 cm
0 0 m
57 0 l
S
1 0 0 1 57 0 cm
0 0 m
64 0 l
S
1 0 0 1 64 0 cm
0 0 m
64 0 l
S
1 0 0 1 64.0001 0 cm
0 0 m
75.759 0 l
S
1 0 0 1 75.684 0.125 cm
1 1 1 RG
0.14999 w
0 0 m
0 42 l
S
1 0 0 1 -336.684 90.625 cm
0 0 m
0 32.375 l
S
1 0 0 1 0 -13.75 cm
0 0 m
0 13.75 l
S
1 0 0 1 0 -11.625 cm
0 0 m
0 11.625 l
S
1 0 0 1 0 -11.625 cm
0 0 m
0 11.625 l
S
1 0 0 1 0 -11.625 cm
0 0 m
0 11.625 l
S
1 0 0 1 0 -42 cm
0 0 m
0 42 l
S
1 0 0 1 336.684 90.625 cm
0 0 m
0 32.375 l
S
1 0 0 1 0 -13.75 cm
0 0 m
0 13.75 l
S
1 0 0 1 0 -11.625 cm
0 0 m
0 11.625 l
S
1 0 0 1 0 -11.625 cm
0 0 m
0 11.625 l
S
1 0 0 1 0 -11.625 cm
0 0 m
0 11.625 l
S
1 0 0 1 -553.2761 -636.9508 cm
BT
0 0 0 rg
/GS0 gs
/T1_2 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
[(Exposur)10 (e status)]TJ
-0.25999 Tw 10.133 2.533 Td
(Anti-)Tj
ET
BT
/Span <>BDC
/T1_2 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
12.19 2.533 Td
( )Tj
EMC
ET
BT
/T1_2 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
12.19001 2.533 Td
(TNF )Tj
0 Tw -2.05701 -1.267 Td
(exposed)Tj
0 -1.267 TD
(5130 PY)Tj
-0.25999 Tw 7.6 2.533 Td
(Anti-)Tj
ET
BT
/Span <>BDC
/T1_2 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
19.79 2.532 Td
( )Tj
EMC
ET
BT
/T1_2 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
19.79001 2.532 Td
(TNF )Tj
0 Tw -2.05701 -1.267 Td
(unexposed)Tj
T*
(10 500 PY)Tj
8.533 2.533 Td
(Thiopurine )Tj
T*
(exposed)Tj
T*
(7300 PY)Tj
8.533 1.267 Td
(Thiopurine unexposed)Tj
T*
(12 000 PY)Tj
/T1_3 1 Tf
-34.8 -1.833 Td
[(Any acute arterial event)-1228 (28 \(5.5\))-4498 (127 \(12.1\))-4763 (43 \(5.9\))]TJ
34.799 0 Td
(175 \(14.6\))Tj
-34.8 -1.55 Td
[(Cerebrov)18 (ascular disease)-1626 (7)]TJ
18.241 0 Td
(15)Tj
8.146 0 Td
(15)Tj
8.921 0 Td
(69)Tj
-35.308 -1.55 Td
[(Ischaemic heart disease)-1276 (20)]TJ
18.241 0 Td
(12)Tj
8.146 0 Td
(25)Tj
8.921 0 Td
(91)Tj
-35.308 -1.55 Td
[(P)37 (eripheral artery disease)-863 (<5)]TJ
18.12 0 Td
(<5)Tj
8.146 0 Td
(<5)Tj
9.521 0 Td
(5)Tj
-35.788 -1.817 Td
(Numbers are events \(incidence rates \(events/1,000 person-)Tj
ET
BT
/Span <>BDC
/T1_3 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
22.221 -8.303 Td
( )Tj
EMC
ET
BT
/T1_3 1 Tf
7.5 0 0 7.5 387.242 627.3033 Tm
(years\)\).)Tj
7.5 0 0 7.5 220.592 689.5758 Tm
24.959 -8.303 Td
( Number of events fewer than \036ve is suppressed )Tj
-24.962 -1.267 Td
[(due to data protection laws)37 (.)37 ( Incidence rates for subtypes of acute arterial events are not given to \
prevent back-)]TJ
ET
BT
/Span <>BDC
/T1_3 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
42.048 -9.57 Td
( )Tj
EMC
ET
BT
/T1_3 1 Tf
7.5 0 0 7.5 220.5695 608.2983 Tm
(calculation of the number of events)Tj
7.5 0 0 7.5 220.592 689.5758 Tm
13.383 -10.837 Td
(.)Tj
-13.386 -1.267 Td
[(PY)129 (,)37 ( person-)]TJ
ET
BT
/Span <>BDC
/T1_3 1 Tf
7.5 0 0 7.5 220.592 689.5758 Tm
4.161 -12.104 Td
( )Tj
EMC
ET
BT
/T1_3 1 Tf
7.5 0 0 7.5 251.7995 598.7958 Tm
(years;)Tj
7.5 0 0 7.5 220.592 689.5758 Tm
6.344 -12.104 Td
[( )55 (TNF)129.1 (,)37 ( tumour necrosis factor)91 (.)]TJ
ET
q
216.592 72.871 336.684 94.661 re
W n
q
/GS1 gs
336.6840478 0 0 94.6618875 216.5920441 72.8707718 cm
1.267 TL /Im0 Do
Q
Q
BT
/T1_2 1 Tf
9 0 0 9 216.592 56.8708 Tm
[(Figur)10 (e 1)]TJ
ET
BT
/Span <>BDC
/T1_2 1 Tf
9 0 0 9 247.201 56.8708 Tm
( )Tj
EMC
ET
BT
/T1_3 1 Tf
9 0 0 9 256.201 56.8708 Tm
(HRs for acute arterial events associated with anti-)Tj
ET
BT
/Span <>BDC
/T1_3 1 Tf
9 0 0 9 216.592 56.8708 Tm
23.262 0 Td
( )Tj
EMC
ET
BT
/T1_3 1 Tf
9 0 0 9 425.95 56.8708 Tm
(TNF \(A\) and thiopurines \(B\),)Tj
9 0 0 9 216.592 56.8708 Tm
33.797 0 Td
( strati\036ed )Tj
-33.797 -1.222 Td
[(by acute arterial event type)37.3 (.)36.9 ( )55 (TNF)129.1 (,)37 ( tumour necrosis factor)91.1 (.)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 740.0758 Tm
(2)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 0 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 740.0758 Tm
(Y)Tj
7.5 0 0 7.5 42 740.0758 Tm
[-2106 (atsunenk)25 (o )55 (T)111 (,)37 ( Rey FE,)37 ( Manary MJ)37.1 (,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
[(.)37 ( Human gut )]TJ
1.68 -1.223 Td
[(microbiome viewed across age and geogr)18 (aphy.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
(Nature)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( )Tj
0 -1.223 TD
(2012;486:222\2267.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 712.5583 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 712.5583 Tm
(3)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -3.669 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 712.5583 Tm
(Zheng D)Tj
7.5 0 0 7.5 42 740.0758 Tm
4.698 -3.669 Td
[(,)37 ( Liwinski )55 (T)111 (,)37 ( Elinav E.)37 ( Inter)18 (action between )]TJ
-3.018 -1.223 Td
[(microbiota and immunity in health and disease)37 (.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
(Cell )Tj
T*
(Res)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2020;30:492\226506.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 685.0408 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 685.0408 Tm
(4)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -7.338 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 685.0408 Tm
(Galeotti C)Tj
7.5 0 0 7.5 42 740.0758 Tm
5.311 -7.338 Td
[(,)37 ( Bayry J)37 (.)37 ( )55 (Autoimmune and in\035ammatory )]TJ
-3.631 -1.223 Td
[(diseases following CO)18.1 (VID-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
11.2579 -8.561 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 126.435 675.8683 Tm
(19.)Tj
7.5 0 0 7.5 42 740.0758 Tm
12.421 -8.561 Td
( )Tj
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
(Nat Rev Rheumatol)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( )Tj
-10.741 -1.223 Td
(2020;16:413\2264.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 657.5233 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 657.5233 Tm
(5)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -11.007 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 657.5233 Tm
(F)Tj
7.5 0 0 7.5 42 740.0758 Tm
2.05 -11.007 Td
[(r)18 (ancino MP)128 (.)37 ( Early development of the gut microbiota )]TJ
-0.37 -1.223 Td
[(and immune health.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
[(P)37 (athogens)]TJ
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2014;3:769\22690.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 639.1783 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 639.1783 Tm
(6)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -13.453 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 639.1783 Tm
(Dong )Tj
7.5 0 0 7.5 42 740.0758 Tm
3.811 -13.453 Td
[(Y)128 (,)37 ( Mo X,)37 ( Hu )55 (Y)128 (,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
[(.)37 ( Epidemiology of CO)18 (VID-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
19.85 -13.453 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 190.875 639.1783 Tm
(19 )Tj
-18.17 -1.223 Td
(among children in China.)Tj
7.5 0 0 7.5 42 740.0758 Tm
10.772 -14.676 Td
( )Tj
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
[(P)37 (ediatrics)]TJ
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
[( 2020;145.)37 ( )]TJ
-9.092 -1.223 Td
[(doi:10.1542/peds)37 (.2020-0702.)36.9 ( [Epub ahead of print:)37 ( )]TJ
T*
(16 Mar 2020].)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 602.4883 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 602.4883 Tm
(7)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -18.345 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 602.4883 Tm
(v)Tj
7.5 0 0 7.5 42 740.0758 Tm
2.052 -18.345 Td
[(an Doorn )55 (AS)36.9 (,)37 ( Meijer B)37 (,)37 ( F)37 (r)18 (ampton CMA,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
-0.037 Tc 0.037 Tw (. )Tj
0 Tc 0 Tw -0.372 -1.223 Td
(Systematic review with meta-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
12.329 -19.568 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 134.4675 593.3158 Tm
(analysis:)Tj
7.5 0 0 7.5 42 740.0758 Tm
15.365 -19.568 Td
( SARS-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
17.809 -19.568 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 584.1433 Tm
(CoV)Tj
7.5 0 0 7.5 42 740.0758 Tm
3.163 -20.791 Td
(-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
3.459 -20.791 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 67.9425 584.1433 Tm
(2 stool testing and the potential for faecal-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
19.05 -20.791 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 574.9708 Tm
(or)Tj
7.5 0 0 7.5 42 740.0758 Tm
2.404 -22.014 Td
[(al tr)18 (ansmission.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
-0.045 Tw [(Aliment )-45 (Pharmacol T)37 (her)]TJ
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
0 Tw ( )Tj
-0.724 -1.223 Td
(2020;52:1276\22688.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 556.6258 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 556.6258 Tm
(8)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -24.46 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 556.6258 Tm
(Al-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
2.736 -24.46 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 62.52 556.6258 Tm
(Sadi R,)Tj
7.5 0 0 7.5 42 740.0758 Tm
5.216 -24.46 Td
[( Dharmapr)18 (akash )55 (V)128 (,)37 ( Nighot P)128 (,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
-0.037 Tc 0.037 Tw (. )Tj
/T1_1 1 Tf
0 Tc 0 Tw -3.536 -1.223 Td
(Bi\036dobacterium bi\036dum)Tj
/T1_0 1 Tf
( Enhances the Intestinal )Tj
T*
[(Epithelial )55 (T)37 (ight Junction Barrier and Protects against )]TJ
T*
[(Intestinal In\035ammation by )55 (T)74 (argeting the )55 (T)37.1 (oll-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
17.8489 -28.129 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 175.8675 529.1083 Tm
(lik)Tj
7.5 0 0 7.5 42 740.0758 Tm
18.646 -28.129 Td
(e )Tj
-16.966 -1.223 Td
[(Receptor)45 (-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
5.136 -29.352 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 80.52 519.9358 Tm
(2 P)Tj
7.5 0 0 7.5 42 740.0758 Tm
6.282 -29.352 Td
[(athw)18 (ay in an NF-)]TJ
/T1_4 1 Tf
(\036)Tj
/T1_0 1 Tf
-0.24001 Tw (B-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
13.846 -29.352 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
13.84599 -29.352 Td
[(Independent )-240 (Manner)91 (.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
0 Tw -12.16599 -1.223 Td
(Int J Mol Sci)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2021;22:8070.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 501.5908 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 501.5908 Tm
(9)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -31.798 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 501.5908 Tm
(Earley H,)Tj
7.5 0 0 7.5 42 740.0758 Tm
4.845 -31.798 Td
[( Lennon G)37 (,)37 ( Balfe )55.1 (\301ine)37 (,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
-0.05499 Tw [(.)37 ( T)37 (he )-55 (abundance )]TJ
0 Tw -3.165 -1.223 Td
[(of )55 (Akk)37 (ermansia muciniphila and its relationship with )]TJ
T*
[(sulphated colonic mucins in health and ulcer)18 (ative )]TJ
T*
[(colitis)37 (.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
(Sci Rep)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2019;9:15683.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 464.9008 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 42 464.9008 Tm
(10)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
0.96 -36.69 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 464.9008 Tm
(Ruiz L,)Tj
7.5 0 0 7.5 42 740.0758 Tm
4.049 -36.69 Td
[( Delgado S)37 (,)37 ( Ruas-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
10.436 -36.69 Td
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 120.27 464.9008 Tm
(Madiedo P)Tj
7.5 0 0 7.5 42 740.0758 Tm
14.2149 -36.69 Td
[(,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
-0.037 Tc 0.037 Tw (. )Tj
0 Tc 0 Tw -12.5349 -1.223 Td
(Bi\037dobacteria and their molecular communication with )Tj
T*
[(the immune system.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
[(F)37 (ront Microbiol)]TJ
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2017;8:2345.)Tj
/T1_3 1 Tf
13.5 0 0 13.5 42 421.1358 Tm
(Risk of acute arterial events )Tj
0 -1.111 TD
(associated with treatment of )Tj
T*
[(in\035ammatory bowel diseases:)37 ( a )]TJ
-0.009 Tw T*
[(nationwide Danish cohort\037)9.3 (study)]TJ
/TT0 1 Tf
0 Tw 9 0 0 9 42 347.9658 Tm
(Kirchgesner )Tj
/TT1 1 Tf
0.00999 Tw 5.396 0 Td
(et al)Tj
/TT0 1 Tf
( recently found that anti-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 42 347.9658 Tm
18.00997 0 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
0.04601 Tw 9 0 0 9 42 336.7968 Tm
(tumour necrosis factor )Tj
9 0 0 9 42 347.9658 Tm
10.10952 -1.241 Td
(\(TNF\) therapy for )Tj
0.226 Tw -10.10952 -1.241 Td
(IBD was associated with a reduced risk )Tj
0 -1.241 TD
[(of )0.5 (a )0.9 (first )0.5 (acute )1.2 (arterial )1.1 (event \(including )]TJ
0.30499 Tw T*
[(ischaemic )0.7 (heart disease, )0.5 (cerebrovascular )]TJ
0.045 Tw T*
[(disease )0.8 (and peripheral )0.8 (artery disease\) )0.8 (in )0.6 (a )]TJ
0.03101 Tw T*
[(nationwide F)35.5 (rench cohort,)]TJ
0 0 1 rg
/GS1 gs
0 Tw 5.967 0 0 5.967 145.2157 284.9958 Tm
(1)Tj
0 0 0 rg
/GS0 gs
0.03101 Tw 9 0 0 9 148.5342 280.9458 Tm
( while the risk )Tj
0.08099 Tw -11.837 -1.241 Td
(was increased compared with the general )Tj
0 Tw T*
(population.)Tj
0 0 1 rg
/GS1 gs
5.967 0 0 5.967 86.6133 262.6558 Tm
(2)Tj
0 0 0 rg
/GS0 gs
0.377 Tw 9 0 0 9 89.9318 258.6058 Tm
[( )0.6 (Nevertheless, a )0.8 (cardiopro)]TJ
0 Tw 12.351 0 Td
(-)Tj
0.10001 Tw -17.677 -1.241 Td
(tective effect of thiopurines could not be )Tj
-0.06 Tw T*
[(ex)22.2 (cluded )0.8 (in )0.6 (the )0.5 (F)35.4 (rench cohort study as )0.7 (risk )]TJ
0.174 Tw T*
[(estimates were )0.5 (at the limits )0.5 (of statistical )]TJ
0.36301 Tw T*
[(significance. )1.4 (The )0.6 (reduction )0.5 (in )0.6 (systemic )]TJ
0.13499 Tw T*
[(inflammation )0.5 (following IBD )0.8 (treatment is )]TJ
0.118 Tw T*
[(thought )-0.8 (to protect against cardiovascular )]TJ
0 Tw T*
(disease,)Tj
0 0 1 rg
/GS1 gs
0.183 Tw 5.967 0 0 5.967 71.2104 184.4658 Tm
(3 4)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 80.5965 180.4158 Tm
[( as elevated )0.6 (C)-23.2 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 141.88286 180.4158 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 141.8775 180.4158 Tm
(reactive )Tj
9 0 0 9 80.5965 180.4158 Tm
10.5944 0 Td
(protein )Tj
-0.05901 Tw -14.8824 -1.241 Td
[(\(CRP\) is )0.5 (now considered to be )0.7 (a )0.7 (cardiovas)]TJ
0 Tw (-)Tj
0.03999 Tw T*
[(cular )0.7 (risk factor)54.7 (.)]TJ
0 0 1 rg
/GS1 gs
5.967 0 0 5.967 105.6403 162.1258 Tm
(5 6)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 114.1737 158.0758 Tm
[( W)118.6 (e sought to establish )]TJ
0.075 Tw -8.019 -1.241 Td
(further evidence regarding cardiovascular )Tj
0.16499 Tw T*
(risk and IBD treatments by investigating )Tj
0.289 Tw T*
[(the risk of acute arterial )0.5 (events associ)]TJ
0 Tw (-)Tj
0.15401 Tw T*
(ated with thiopurines and anti-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 166.0947 113.3998 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 166.0947 113.3998 Tm
(TNF in a )Tj
0 Tw -13.788 -1.241 Td
(nationwide Danish cohort study)Tj
9 0 0 9 114.1737 158.0758 Tm
5.6187 -6.205 Td
(.)Tj
-0.056 Tw -12.6377 -1.241 Td
(Using Danish nationwide registers,)Tj
0 0 1 rg
/GS1 gs
5.967 0 0 5.967 183.1776 95.1058 Tm
(7 8)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 191.1372 91.0558 Tm
( we )Tj
0.14101 Tw -16.571 -1.241 Td
[(assembled )0.5 (a )0.5 (cohort of patients with IBD )]TJ
0.00301 Tw T*
(aged 18 years or older in Denmark, in the )Tj
0.24001 Tw T*
[(period 2005\22620)-0.9 (18 \(online supplemental )]TJ
0.269 Tw T*
[(methods\). W)118.7 (e )0.6 (defined )0.6 (current exposure )]TJ
0.379 Tw 19.399 56.983 Td
(to either anti-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 275.4852 559.2268 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 275.4852 559.2268 Tm
(TNF \(30 days from the )Tj
0.209 Tw -6.544 -1.222 Td
(date )Tj
9 0 0 9 191.1372 91.0558 Tm
5.1304 50.797 Td
[(of administration of golimumab )0.7 (or )]TJ
0.164 Tw -2.3024 -1.222 Td
[(adalimumab )0.6 (and 60 days for infliximab\) )]TJ
0.33701 Tw 0 -1.222 TD
[(or thiopurines \(estimated from )-0.7 (defined )]TJ
0.256 Tw T*
(daily doses for azathioprine and tablets )Tj
-0.009 Tw T*
[(dispensed for mercaptopurine\). Currently)114.3 (, )]TJ
0.147 Tw T*
(exposed subjects were matched 1:1 with )Tj
0.138 Tw T*
[(unexposed subjects )0.6 (\(who )0.5 (did )0.5 (not receive )]TJ
0.642 Tw T*
(the treatment modelled\) on propen)Tj
0 Tw (-)Tj
0.26401 Tw T*
(sity scores \(PSs\) estimated from covari)Tj
0 Tw (-)Tj
0.31 Tw T*
[(ates including basic demograph)-0.7 (ics, IBD )]TJ
0.295 Tw T*
[(subtype and duration, other )-0.6 (IBD treat)]TJ
0 Tw (-)Tj
-0.032 Tw T*
[(ments, IBD)-36.6 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
7.9876 37.355 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 263.0292 427.2508 Tm
(related endoscopy )Tj
9 0 0 9 191.1372 91.0558 Tm
15.975 37.355 Td
(or imaging, )Tj
0.30299 Tw -13.147 -1.222 Td
(comorbidities and traditional cardiovas)Tj
0 Tw (-)Tj
0.23399 Tw T*
[(cular )1 (risk )0.8 (factors, )0.5 (all )1.1 (assessed at )0.6 (cohort )]TJ
0.02 Tw T*
[(entry)114.2 (. )0.7 (Thus, )0.7 (we )0.7 (constructed a )0.7 (cohort with )]TJ
0.395 Tw T*
[(subjects )0.7 (matched )0.5 (on PSs for exposure )]TJ
0.34 Tw T*
(to anti-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 246.9282 372.2608 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 246.9282 372.2608 Tm
(TNF and another with )Tj
9 0 0 9 191.1372 91.0558 Tm
17.54149 31.245 Td
(subjects )Tj
0 Tw -14.71349 -1.222 Td
(matched for exposure to thiopurines.)Tj
0.271 Tw 1 -1.241 Td
[(Subjects )0.8 (were )0.8 (followed )0.9 (for their first )]TJ
0.009 Tw -1 -1.241 Td
[(acute arterial event, specifically)115.6 (, ischaemic )]TJ
0.054 Tw 0 -1.241 TD
[(heart disease, )0.8 (cerebrovascular )0.5 (disease )0.6 (and )]TJ
0.383 Tw T*
[(peripheral )0.5 (artery disease. )0.9 (HRs for the )]TJ
0.239 Tw T*
(outcomes associated with either thiopu)Tj
0 Tw (-)Tj
0.25999 Tw T*
(rines or anti-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 270.0942 294.2488 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 270.0942 294.2488 Tm
(TNF were )Tj
9 0 0 9 191.1372 91.0558 Tm
13.97449 22.577 Td
(estimated using )Tj
0.28999 Tw -11.14649 -1.241 Td
[(Co)21.6 (x )0.6 (models )0.5 (to account )0.7 (for death as )0.6 (a )]TJ
0.369 Tw T*
[(competing risk )0.5 (and adjust for cortico)]TJ
0 Tw (-)Tj
0.19099 Tw T*
[(steroid use, IBD)-36.3 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
10.45529 18.854 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 285.2322 260.7418 Tm
(related hospital activity )Tj
0.16701 Tw -7.627 -1.241 Td
(\(inpatient admission or surgery\) )Tj
9 0 0 9 191.1372 91.0558 Tm
17.43283 17.613 Td
(and use )Tj
0.22301 Tw -14.60483 -1.241 Td
[(of the \221other)-36.9 (\222 treatment \(ie, )0.5 (thiopurines )]TJ
0.27299 Tw T*
[(in )0.5 (the anti-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 262.9482 227.2348 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 262.9482 227.2348 Tm
(TNF )Tj
9 0 0 9 191.1372 91.0558 Tm
10.58549 15.131 Td
[(cohort and vice )0.7 (versa\) )]TJ
0.642 Tw -7.75749 -1.241 Td
[(as )0.5 (time-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
6.8145 13.89 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 252.4632 216.0658 Tm
(dependent covariates )Tj
9 0 0 9 191.1372 91.0558 Tm
17.4075 13.89 Td
(assessed )Tj
-0.04401 Tw -14.5795 -1.241 Td
[(prospectively in )0.7 (follow-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
12.88329 12.649 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 307.0842 204.8968 Tm
(up )Tj
9 0 0 9 191.1372 91.0558 Tm
14.21849 12.649 Td
[(time. )0.8 (HRs were )]TJ
0.03799 Tw -11.39049 -1.241 Td
(also estimated separately for an induction )Tj
-0.01801 Tw 19.399 40.617 Td
(period \(<6-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
27.33999 52.025 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 437.1972 559.2808 Tm
(month )Tj
9 0 0 9 191.1372 91.0558 Tm
30.42359 52.025 Td
(follow-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
33.51359 52.025 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 492.7542 559.2808 Tm
(up\) and a main)Tj
0 Tw 9 0 0 9 191.1372 91.0558 Tm
39.90398 52.025 Td
(-)Tj
/C2_0 1 Tf
-17.67798 -1.241 Td
<00570048005100440051004600480003005300480055004C005200470003000B0095001900030050005200510057004B0056000C0011>Tj
/TT0 1 Tf
1.19901 Tw 1 -1.241 Td
[(Overall, )0.9 (our nationwide cohort )]TJ
0.065 Tw -1 -1.241 Td
(comprised 63)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
28.119 48.302 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 445.3332 525.7738 Tm
(167 patients with IBD. )Tj
9 0 0 9 191.1372 91.0558 Tm
38.55031 48.302 Td
(The )Tj
-0.048 Tw -16.32431 -1.241 Td
[(thiopurine cohort included )0.9 (7,840 subjects, )]TJ
0.15199 Tw T*
(and the anti-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 442.0752 503.4358 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 442.0752 503.4358 Tm
(TNF cohort included 6,458 )Tj
0.009 Tw -5.656 -1.241 Td
(subjects )Tj
9 0 0 9 191.1372 91.0558 Tm
25.8104 44.579 Td
[(\(online )0.5 (supplemental )0.7 (tabl)0.5 (es 1 and )]TJ
0.25101 Tw -3.5844 -1.222 Td
[(2\). F)49.6 (ollow-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
27.20241 43.357 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 435.9552 481.2688 Tm
(up time contributed by each )Tj
0.29201 Tw -4.976 -1.222 Td
(exposure group, number of events )Tj
9 0 0 9 191.1372 91.0558 Tm
38.65464 42.135 Td
(and )Tj
0 Tw -16.42864 -1.241 Td
(incidence rates are shown in )Tj
0 0 1 rg
/GS1 gs
12.393 0 Td
(table)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
36.684 40.894 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
36.962 40.894 Td
(1)Tj
0 0 0 rg
/GS0 gs
0.555 0 Td
(.)Tj
0.134 Tw -14.292 -1.241 Td
[(Current use )0.5 (of thiopurines was )0.8 (associ)]TJ
0 Tw (-)Tj
0.186 Tw -1 -1.241 Td
[(ated )0.8 (with )0.5 (a )1 (significantly )1.2 (reduced )0.7 (risk )0.9 (of )]TJ
0.258 Tw T*
[(acute )0.5 (arterial events \(HR 0.39; 95%)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
39.04948 37.171 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 543.7122 425.5948 Tm
(CI )Tj
0.16 Tw -16.95 -1.241 Td
(0.24 to 0.65\), which )Tj
9 0 0 9 191.1372 91.0558 Tm
31.95351 35.93 Td
[(was )0.6 (greater during )]TJ
0.373 Tw -9.72851 -1.241 Td
(the induction period than the mainte)Tj
0 Tw (-)Tj
0.409 Tw T*
[(nance )0.8 (period \(HR )0.7 (0.14; 95%)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
36.41749 33.448 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 520.0152 392.0878 Tm
(CI )Tj
9 0 0 9 191.1372 91.0558 Tm
38.2885 33.448 Td
(0.05 )Tj
0.258 Tw -16.0635 -1.241 Td
(to 0.39 and HR 0.56; 95%)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
35.14398 32.207 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 508.5762 380.9188 Tm
(CI 0.32 to )Tj
0.64 Tw -13.046 -1.241 Td
(0.99, respectively\), relative )Tj
9 0 0 9 191.1372 91.0558 Tm
35.9875 30.966 Td
(to unex)Tj
0 Tw (-)Tj
0.202 Tw -13.7625 -1.241 Td
[(posed patients. )0.8 (Anti-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 473.5482 358.5808 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 473.5482 358.5808 Tm
(TNF )Tj
9 0 0 9 191.1372 91.0558 Tm
33.9144 29.725 Td
[(was )0.9 (also )0.8 (asso)]TJ
0 Tw (-)Tj
0.312 Tw -11.6894 -1.241 Td
[(ciated )0.8 (with a )0.6 (significantly )0.5 (reduced risk )]TJ
0.17 Tw T*
(\(HR 0.41; 95%)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
29.282 27.243 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 455.8002 336.2428 Tm
(CI 0.24 to 0.71\), which )Tj
0.142 Tw -7.182 -1.241 Td
(differed little )Tj
9 0 0 9 191.1372 91.0558 Tm
28.3925 26.002 Td
[(between )0.5 (the induction and )]TJ
0.276 Tw -6.1675 -1.241 Td
[(the maintenance )0.6 (period \()]TJ
0 0 1 rg
/GS1 gs
(figure)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 191.1372 91.0558 Tm
36.2764 24.761 Td
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 522.5982 313.9048 Tm
(1)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 191.1372 91.0558 Tm
37.385 24.761 Td
[(\). )0.7 (The )]TJ
0.16499 Tw -15.16 -1.222 Td
[(risks of subtypes of acute )0.8 (arterial )0.7 (events )]TJ
0.134 Tw 0 -1.222 TD
(were consistent for both treatments, and )Tj
0.313 Tw T*
[(results were )0.5 (consistent across subgroup )]TJ
0.049 Tw T*
[(analyses )0.8 (by )0.5 (sex, )0.9 (IBD )1 (type and )0.6 (age )0.8 (\(online )]TJ
0 Tw 0 -1.241 TD
(supplemental figure 1\).)Tj
0.09399 Tw 1 -1.241 Td
[(In addition to the previous )-0.7 (nationwide )]TJ
0.50301 Tw -1 -1.241 Td
[(F)35.4 (rench cohort study)114.3 (,)]TJ
0 0 1 rg
/GS1 gs
0 Tw 5.967 0 0 5.967 479.3309 240.3629 Tm
(1)Tj
0 0 0 rg
/GS0 gs
0.50301 Tw 9 0 0 9 482.6494 236.3129 Tm
( our nationwide )Tj
0.047 Tw -10.163 -1.222 Td
[(Danish )0.5 (cohort study provides evidence )0.6 (of )]TJ
0.157 Tw 0 -1.222 TD
[(a )0.5 (cardioprotective effect )0.5 (of both thiopu)]TJ
0 Tw (-)Tj
-0.02 Tw T*
(rine and anti-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 442.0324 203.3189 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 442.0324 203.3189 Tm
(TNF therapy for IBD )Tj
9 0 0 9 482.6494 236.3129 Tm
4.82738 -3.666 Td
(\(online )Tj
0.065 Tw -14.99038 -1.222 Td
[(supplemental )0.6 (discussion\). )0.6 (The )0.6 (association )]TJ
ET
q
1 0 0 1 213.67 43.393 cm
0 g
0 G
1 w
/GS4 gs
0 Tw /Fm0 Do
Q
q
1 0 0 1 38.439 43.961 cm
0 g
0 G
1 w
/GS4 gs
0 Tw /Fm1 Do
Q
BT
0 g
/GS4 gs
/T1_5 1 Tf
0 Tw 0 -9 9 0 578 290.19679 Tm
( on November 6, 2023 by guest. Protected by copyright.)Tj
0 0 1 rg
/GS4 gs
-8.22598 0 Td
(http://gut.bmj.com/)Tj
0 g
/GS4 gs
-40.13193 0 Td
(Gut: first published as 10.1136/gutjnl-2021-326599 on 8 February 2022. D\
ownloaded from )Tj
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ET
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BT
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BT
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(12 )Tj
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ET
BT
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[( )-1000 ( )]TJ
EMC
ET
BT
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(24 )Tj
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[(4 \(15.4 %\))-4298 (2 \(15.4 %\))]TJ
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ET
BT
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[( )-1000 ( )]TJ
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ET
BT
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ET
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[( )-1000 ( )]TJ
EMC
ET
BT
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(0 \(0%\))Tj
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[( )-945 ( )]TJ
EMC
ET
BT
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(Ye)Tj
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ET
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[( )-1000 ( )]TJ
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BT
/T1_3 1 Tf
6.5 0 0 6.5 227.05294 50.0073 Tm
(No)Tj
0 Tw 27.61501 0 Td
(18 \(69.2 %\))Tj
6.5 0 0 6.5 220.592 344.3208 Tm
37.378 -45.279 Td
(9 \(69.2 %\))Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 740.0758 Tm
(3)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 740.0758 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 740.0758 Tm
[(Boulling )55 (A,)37 ( Sato M,)37 ( Masson E,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
[(.)37 ( Identi\037cation )]TJ
0 -1.219 TD
(of a functional PRSS1 promoter v)Tj
7.5 0 0 7.5 42 740.0758 Tm
13.663 -1.219 Td
(ariant in linkage )Tj
-11.983 -1.219 Td
(disequilibrium with the chronic pancreatitis-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 173.9175 721.7908 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 173.9175 721.7908 Tm
(protecting )Tj
-15.909 -1.219 Td
[(rs10273639.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
6.593 -3.657 Td
(Gut)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2015;64:1837\2268.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 703.5058 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 703.5058 Tm
(4)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 703.5058 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 703.5058 Tm
[(Derikx MH,)37 ( K)]TJ
7.5 0 0 7.5 42 740.0758 Tm
6.401 -4.876 Td
[(ov)18 (acs P)128 (,)37 ( Scholz M,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
[(.)37 ( P)37 (olymorphisms at )]TJ
-4.721 -1.219 Td
(PRSS1-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 74.0325 694.3633 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 74.0325 694.3633 Tm
(PRSS2 and CLDN2-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 126.5025 694.3633 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 126.5025 694.3633 Tm
(MORC4 loci associate with )Tj
-9.587 -1.219 Td
(alcoholic and non-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 105.0225 685.2208 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 105.0225 685.2208 Tm
(alcoholic chronic pancreatitis in a )Tj
-6.723 -1.219 Td
[(European replication study.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
7.5 0 0 7.5 42 740.0758 Tm
11.772 -8.533 Td
(Gut)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2015;64:1426\22633.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 666.9358 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 666.9358 Tm
(5)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 666.9358 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 666.9358 Tm
[(Whitcomb DC)37 (,)]TJ
7.5 0 0 7.5 42 740.0758 Tm
6.885 -9.752 Td
[( LaRusch J)37 (,)37 ( Kr)18 (asinskas )55 (AM,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
-0.037 Tc 0.037 Tw (. )Tj
0 Tc 0 Tw -5.205 -1.219 Td
[(Common genetic v)18 (ariants in the CLDN2 and PRSS1-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 195.5625 657.7933 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 648.6508 Tm
(PRSS2 loci alter risk for alcohol-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 141.1275 648.6508 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 141.1275 648.6508 Tm
[(related and spor)18 (adic )]TJ
-11.537 -1.219 Td
(pancreatitis)Tj
7.5 0 0 7.5 42 740.0758 Tm
5.847 -13.409 Td
[(.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
-0.01801 Tw (Nat Genet)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
0 Tw ( 2012;44:1349\22654.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 630.3658 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 630.3658 Tm
(6)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 630.3658 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 630.3658 Tm
[(Herzig )55 (AF)]TJ
7.5 0 0 7.5 42 740.0758 Tm
4.997 -14.628 Td
[(,)37 ( G\351nin E,)37 ( Cooper DN)37 (,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
[(.)37 ( Role of the )]TJ
-3.317 -1.219 Td
(Common )Tj
/T1_1 1 Tf
-0.24001 Tw (PRSS1-)Tj
ET
BT
/Span <>BDC
/T1_1 1 Tf
7.5 0 0 7.5 100.5825 621.2233 Tm
( )Tj
EMC
ET
BT
/T1_1 1 Tf
7.5 0 0 7.5 100.58243 621.2233 Tm
(PRSS2)Tj
/T1_0 1 Tf
0 Tw 7.5 0 0 7.5 42 740.0758 Tm
10.10599 -15.847 Td
[( Haplotype in )55 (Alcoholic )]TJ
-8.42599 -1.219 Td
(and Non-)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 80.295 612.0808 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 80.295 612.0808 Tm
[(Alcoholic Chronic P)37 (ancreatitis:)]TJ
7.5 0 0 7.5 42 740.0758 Tm
16.034 -17.066 Td
( Meta- )Tj
-0.24001 Tw -14.354 -1.219 Td
[(and )-240 (Re-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 75.83992 602.9383 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 75.83992 602.9383 Tm
(Analyses)Tj
7.5 0 0 7.5 42 740.0758 Tm
7.64199 -18.285 Td
[(.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
0 Tw 0.44301 0 Td
(Genes)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
[( 2020;11.)37 ( doi:10.3390/)]TJ
-6.405 -1.219 Td
[(genes11111349.)37 ( [Epub ahead of print:)37 ( 13 11 2020].)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 584.6533 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 584.6533 Tm
(7)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 584.6533 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 584.6533 Tm
[(Y)74 (adav D)]TJ
7.5 0 0 7.5 42 740.0758 Tm
4.606 -20.723 Td
[(,)37 ( )55 (Whitcomb DC)37 (.)37 ( )55 (T)37 (he role of alcohol and )]TJ
-2.926 -1.219 Td
[(smoking in pancreatitis)37 (.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
[(Nat Rev )18 (Gastroenterol Hepatol)]TJ
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( )Tj
T*
(2010;7:131\22645.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
-0.24001 Tw 7.5 0 0 7.5 42 557.2258 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 557.2258 Tm
(8)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 557.2258 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 557.2258 Tm
[(Zou )-185 (W-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 74.32493 557.2258 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 74.32493 557.2258 Tm
(B)Tj
7.5 0 0 7.5 42 740.0758 Tm
4.77299 -24.38 Td
[(,)37 ( )-185 (W)37 (ang )-185 (Y)111 (-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 103.06485 557.2258 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 103.06477 557.2258 Tm
(C)Tj
7.5 0 0 7.5 42 740.0758 Tm
8.64197 -24.38 Td
[(,)37 ( )-240 (Ren )-240 (X-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 128.4672 557.2258 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 128.4672 557.2258 Tm
(L,)Tj
7.5 0 0 7.5 42 740.0758 Tm
12.12106 -24.38 Td
( )Tj
/T1_1 1 Tf
0 Tw 0.23994 0 Td
(et\037al)Tj
/T1_0 1 Tf
-0.05499 Tw [(.)37 ( T)73.9 (rpv6 )-55 (v)18 (ariants )]TJ
0 Tw -10.681 -1.219 Td
(confer susceptibility to chronic pancreatitis in the )Tj
T*
[(Chinese population.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
(Hum Mutat)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2020;41:1351\2267.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
-0.24001 Tw 7.5 0 0 7.5 42 529.7983 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 45.6 529.7983 Tm
(9)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 529.7983 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 529.7983 Tm
[(Zou )-185 (W-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 74.32493 529.7983 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 74.32493 529.7983 Tm
(B)Tj
7.5 0 0 7.5 42 740.0758 Tm
4.77299 -28.037 Td
[(,)37 ( )-185 (T)74 (ang )-240 (X-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 101.53485 529.7983 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 101.53477 529.7983 Tm
(Y)Tj
7.5 0 0 7.5 42 740.0758 Tm
8.30997 -28.037 Td
[(,)37 ( )-240 (Zhou )-240 (D-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 129.5922 529.7983 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 129.5922 529.7983 Tm
(Z,)Tj
7.5 0 0 7.5 42 740.0758 Tm
12.32596 -28.037 Td
( )Tj
/T1_1 1 Tf
0 Tw 0.24004 0 Td
(et\037al)Tj
/T1_0 1 Tf
[(.)37 ( SPINK1,)37.1 ( PRSS1,)37 ( )]TJ
-10.886 -1.219 Td
[(CTRC)37 (,)37 ( and CFTR genotypes in\035uence disease onset )]TJ
T*
[(and clinical outcomes in chronic pancreatitis)37 (.)37 ( )]TJ
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
(Clin )Tj
-0.01801 Tw T*
[(T)74 (r)18 (ansl Gastroenterol)]TJ
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
0 Tw ( 2018;9:204.)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 42 493.2283 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 42 493.2283 Tm
(10)Tj
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 49.2 493.2283 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 54.6 493.2283 Tm
[(Lewis MD)37 (,)]TJ
7.5 0 0 7.5 42 740.0758 Tm
5.4011 -32.913 Td
[( )55.1 (T)73.9 (alluri J)37 (,)37 ( )55 (Wilco)9 (x CM,)37 ( )]TJ
/T1_1 1 Tf
(et\037al)Tj
/T1_0 1 Tf
[(.)37 ( Differences in )]TJ
-3.7211 -1.219 Td
[(age at onset of symptoms)37 (,)37 ( and effects of genetic )]TJ
T*
[(v)18 (ariants)37 (,)37 ( in patients with early vs late-)]TJ
ET
BT
/Span <>BDC
/T1_0 1 Tf
7.5 0 0 7.5 157.5075 474.9433 Tm
( )Tj
EMC
ET
BT
/T1_0 1 Tf
7.5 0 0 7.5 157.5075 474.9433 Tm
(onset idiopathic )Tj
-13.721 -1.219 Td
[(chronic pancreatitis in a North )55 (American cohort.)]TJ
7.5 0 0 7.5 42 740.0758 Tm
19.015 -36.57 Td
( )Tj
0 0 1 rg
/GS1 gs
/T1_1 1 Tf
(Clin )Tj
-17.335 -1.219 Td
(Gastroenterol Hepatol)Tj
0 0 0 rg
/GS0 gs
/T1_0 1 Tf
( 2021;19:349\22657.)Tj
/T1_3 1 Tf
13.5 0 0 13.5 42 431.2358 Tm
(Gut microbiota changes are )Tj
0 -1.111 TD
(detected in asymptomatic very )Tj
T*
(young children with SARS-)Tj
ET
BT
/Span <>BDC
/T1_3 1 Tf
13.5 0 0 13.5 177.459 401.2388 Tm
( )Tj
EMC
ET
BT
/T1_3 1 Tf
-0.24001 Tw 13.5 0 0 13.5 42 386.2403 Tm
[(CoV)45 (-)]TJ
ET
BT
/Span <>BDC
/T1_3 1 Tf
13.5 0 0 13.5 66.3945 386.2403 Tm
( )Tj
EMC
ET
BT
/T1_3 1 Tf
13.5 0 0 13.5 66.39436 386.2403 Tm
(2\037infection)Tj
/TT0 1 Tf
0.315 Tw 9 0 0 9 42 358.2358 Tm
[(W)118.7 (e read with great interest the recent )]TJ
0.153 Tw 0 -1.238 TD
[(article )1 (by Y)123.6 (eoh )]TJ
/TT1 1 Tf
0.03 Tc (et al)Tj
/TT0 1 Tf
[(, )0.5 (demonstrating )0.5 (an)29.9 ( )]TJ
0.214 Tw T*
[(altered stool microbiome composition)29.9 ( )]TJ
0.185 Tw T*
[(in )0.6 (patients )0.6 (with )0.5 (CO)27 (VID)-36.6 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 148.89174 324.8098 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 148.893 324.8098 Tm
[(19 )0.5 (compared)]TJ
9 0 0 9 42 358.2358 Tm
18.00968 -3.714 Td
( )Tj
0.35899 Tw -18.00968 -1.238 Td
[(with controls, with greater dysbiosis)29.9 ( )]TJ
0.065 Tw T*
[(correlating with elevated inflammatory)29.7 ( )]TJ
-0.03 Tw T*
(markers.)Tj
0 0 1 rg
/GS1 gs
0 Tc 0 Tw 5.967 0 0 5.967 77.5848 295.4458 Tm
(1)Tj
0 0 0 rg
/GS0 gs
0.03 Tc 0.39999 Tw 9 0 0 9 81.0824 291.3958 Tm
[( )0.6 (A)17.6 (dditionally)114.5 (, )0.6 (dysbiosis )0.6 (was)29.8 ( )]TJ
0 Tw -4.342 -1.238 Td
(seen after disease resolution.)Tj
0 0 1 rg
/GS1 gs
0 Tc 5.967 0 0 5.967 160.2182 284.3058 Tm
(1)Tj
0 0 0 rg
/GS0 gs
0.03 Tc 0.84599 Tw 9 0 0 9 51 269.1158 Tm
[(T)132.8 (o )0.5 (our )0.6 (knowledge, )0.6 (gut )0.6 (micro)]TJ
0 Tc 0 Tw (-)Tj
0.03 Tc 0.21899 Tw -1 -1.238 Td
[(biome )0.5 (studies )0.5 (in )0.5 (young )0.5 (children )0.5 (with)29.8 ( )]TJ
0.438 Tw T*
[(CO)27 (VID)-36.6 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 76.90731 246.8318 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 76.911 246.8318 Tm
[(19 )0.6 (have )]TJ
9 0 0 9 51 269.1158 Tm
7.6398 -2.476 Td
[(not )0.7 (been )0.6 (reported.)30.2 ( )]TJ
0.367 Tw -8.6398 -1.238 Td
[(Critically)114.5 (, )0.6 (the )0.6 (developing )0.6 (gut )0.5 (micro)]TJ
0 Tc 0 Tw (-)Tj
0.03 Tc 0.26199 Tw T*
[(biome of very young children differs)29.9 ( )]TJ
0.427 Tw T*
[(from adults and establishes immune)30.1 ( )]TJ
0.244 Tw T*
[(and )0.5 (inflammatory )0.5 (pathways.)]TJ
0 0 1 rg
/GS1 gs
5.967 0 0 5.967 163.2618 206.3258 Tm
(2 3)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 173.5482 202.2758 Tm
( More)Tj
0 Tc 0 Tw (-)Tj
0.03 Tc 0.532 Tw -14.616 -1.238 Td
[(over)54.6 (, children with CO)27 (VID)-36.5 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 172.22394 191.1338 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 172.2342 191.1338 Tm
[(19 can)29.9 ( )]TJ
0.112 Tw -14.47 -1.238 Td
(subsequently )Tj
9 0 0 9 173.5482 202.2758 Tm
-8.35172 -2.476 Td
[(develop )0.7 (autoimmune )0.7 (and)29.8 ( )]TJ
0.70599 Tw -6.26428 -1.238 Td
[(autoinflammatory diseases including)29.8 ( )]TJ
-0.05499 Tw T*
[(Multisystem Inflammatory Syndrome )0.5 (in)29.9 ( )]TJ
-0.308 Tw T*
[(Children )-317.3 (\(MIS-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 104.91672 146.5658 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 104.91672 146.5658 Tm
(C\))Tj
0 0 1 rg
/GS1 gs
0.009 Tw 5.967 0 0 5.967 114.9506 150.6258 Tm
(4 5)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 123.8388 146.5758 Tm
[(, which may in part)29.9 ( )]TJ
0.14301 Tw -9.093 -1.238 Td
[(be microbiome mediated, given recent)29.9 ( )]TJ
0.03101 Tw T*
[(findings by Y)123.6 (eoh )]TJ
/TT1 1 Tf
(et al)Tj
/TT0 1 Tf
0 Tc 0 Tw (.)Tj
0 0 1 rg
/GS1 gs
5.967 0 0 5.967 134.4351 128.3458 Tm
(1)Tj
0 0 0 rg
/GS0 gs
0.03 Tc 0.03101 Tw 9 0 0 9 137.9326 124.2958 Tm
[( It is difficult to)29.9 ( )]TJ
0.164 Tw -10.659 -1.238 Td
[(study this in young children, as many)29.7 ( )]TJ
0.069 Tw T*
(with SARS-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 89.33251 102.0118 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 89.3236 102.0118 Tm
[(CoV)67.7 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 110.6293 102.0118 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 110.6356 102.0118 Tm
(2 infection are asymp)Tj
0 Tc 0 Tw (-)Tj
0.03 Tc -7.626 -1.238 Td
(tomatic and rarely tested.)Tj
0 0 1 rg
/GS1 gs
0 Tc 5.967 0 0 5.967 147.207 94.9259 Tm
(6)Tj
0 0 0 rg
/GS0 gs
0.03 Tc 0.08501 Tw 9 0 0 9 51 79.7358 Tm
[(T)132.8 (o address this, knowing that SARS-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 204.09 79.7358 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
-0.097 Tw 9 0 0 9 42 68.5938 Tm
[(CoV)67.7 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 63.3057 68.5938 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 63.312 68.5938 Tm
[(2 )0.5 (can )]TJ
9 0 0 9 51 79.7358 Tm
3.93299 -1.238 Td
[(be )0.5 (detected )0.5 (in )0.5 (stool,)]TJ
0 0 1 rg
/GS1 gs
0 Tc 0 Tw 5.967 0 0 5.967 167.0803 72.6458 Tm
(7)Tj
0 0 0 rg
/GS0 gs
0.03 Tc -0.097 Tw 9 0 0 9 170.5778 68.5958 Tm
[( )0.5 (we )0.6 (used)29.8 ( )]TJ
0.3 Tw -14.286 -1.238 Td
(an established study collecting longi)Tj
0 Tc 0 Tw (-)Tj
0.03 Tc 0.13901 Tw T*
[(tudinal )0.8 (stool )0.7 (samples )0.7 (from )0.7 (before )0.7 (and)29.9 ( )]TJ
0.008 Tw 19.399 76.95 Td
[(throughout the pandemic to investigate)30.1 ( )]TJ
0.306 Tw 0 -1.222 TD
[(the )0.6 (prevalence )0.7 (and )0.7 (associated )0.7 (micro)]TJ
0 Tc 0 Tw (-)Tj
0.03 Tc 0.10899 Tw T*
(biome changes of SARS-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 319.24835 716.8658 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 319.2398 716.8658 Tm
[(CoV)67.7 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 340.5455 716.8658 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 340.5518 716.8658 Tm
[(2 in very)29.7 ( )]TJ
-0.005 Tw -13.772 -1.222 Td
(young children. W)Tj
9 0 0 9 170.5778 68.5958 Tm
13.49227 70.808 Td
(e ran the CDC 2019-)Tj
ET
BT
/Span <>BDC
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9 0 0 9 378.6938 705.8678 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
0.142 Tw 9 0 0 9 216.6038 694.8698 Tm
[(Novel Coronavirus R)22.1 (eal-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 320.7518 694.8698 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 320.7518 694.8698 Tm
[(T)49.8 (ime R)]TJ
9 0 0 9 170.5778 68.5958 Tm
20.12849 69.586 Td
[(T)95.8 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 360.41201 694.8698 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 360.4058 694.8698 Tm
[(PCR)30.1 ( )]TJ
0.30901 Tw -15.978 -1.222 Td
(Diagnostic P)Tj
9 0 0 9 170.5778 68.5958 Tm
11.12749 68.364 Td
[(anel assay on 769 serial)30.2 ( )]TJ
0.175 Tw -6.01349 -1.222 Td
[(stool samples from 595 children aged)29.9 ( )]TJ
0.201 Tw T*
[(0\22624 months collected from F)49.6 (ebruary)29.8 ( )]TJ
-0.02499 Tw T*
[(2020 to F)49.5 (ebruary 2021. The prevalence)30.1 ( )]TJ
0.034 Tw T*
(of SARS-)Tj
ET
BT
/Span <>BDC
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( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 253.8278 639.8798 Tm
[(CoV)67.7 (-)]TJ
ET
BT
/Span <>BDC
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9 0 0 9 275.1335 639.8798 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 275.1398 639.8798 Tm
[(2 in faeces was 1.7% \(13)29.8 ( )]TJ
0.5 Tw -6.503 -1.222 Td
(samples from 13 separate children\))Tj
9 0 0 9 170.5778 68.5958 Tm
23.12406 62.254 Td
( )Tj
0.22701 Tw -18.00906 -1.222 Td
[(with )0.5 (prevalence )0.5 (at)]TJ
ET
BT
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( )Tj
EMC
ET
BT
/TT0 1 Tf
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(<2)Tj
ET
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9 0 0 9 313.9748 617.8838 Tm
( )Tj
EMC
ET
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/TT0 1 Tf
9 0 0 9 315.3698 617.8838 Tm
[(days )0.5 (and )]TJ
9 0 0 9 170.5778 68.5958 Tm
20.832 61.032 Td
[(2, )0.5 (6,)30.1 ( )]TJ
0.286 Tw -15.717 -1.222 Td
[(12 and 24 months of 0% \(0/1\), 0%)30 ( )]TJ
-0.03 Tw T*
[(\(0/21\), 2.6% \(4/156\), 2.0% \(7/357\) and)29.8 ( )]TJ
0.3 Tw T*
[(0.9%,\(2/234\), respectively)114.5 (. P)17.4 (revalence)30.1 ( )]TJ
0.23599 Tw T*
(by month is shown in online supple)Tj
0 Tc 0 Tw (-)Tj
0.03 Tc -0.011 Tw T*
[(mental )0.7 (figure )0.7 (1A, )0.7 (with )0.7 (the )0.7 (first )0.7 (positive)30.1 ( )]TJ
-0.028 Tw T*
[(sample detected 31 days before the first)29.9 ( )]TJ
0.064 Tw T*
[(reported case of CO)27 (VID)-36.6 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 322.36784 540.8978 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 322.3808 540.8978 Tm
[(19 regionally)114.6 (.)]TJ
9 0 0 9 170.5778 68.5958 Tm
23.12528 52.478 Td
( )Tj
0.233 Tw -18.01028 -1.222 Td
[(No samples were positive in controls)29.8 ( )]TJ
-0.036 Tw T*
[(collected prior to the pandemic in 2019)29.9 ( )]TJ
-0.058 Tw T*
[(\(n=97 samples from 66 individuals\). Of)30 ( )]TJ
0.22301 Tw T*
[(13 )0.6 (positive )0.5 (children, )0.5 (12 )0.6 (were )0.5 (asymp)]TJ
0 Tc 0 Tw (-)Tj
0.03 Tc 0.423 Tw T*
[(tomatic with no personal or family)29.8 ( )]TJ
0.166 Tw T*
(history of SARS-)Tj
ET
BT
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( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 287.9018 474.9098 Tm
[(CoV)67.7 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 309.2075 474.9098 Tm
( )Tj
EMC
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(2 \()Tj
0 0 1 rg
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(table)Tj
ET
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/Span <>BDC
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9 0 0 9 341.95571 474.9098 Tm
( )Tj
EMC
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(1A)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 170.5778 68.5958 Tm
20.79899 45.146 Td
[(\). Of)30 ( )]TJ
0.23 Tw -15.68399 -1.222 Td
[(13 children, 1 was symptomatic with)29.8 ( )]TJ
0.27499 Tw T*
[(CO)27 (VID)-36.6 (-)]TJ
ET
BT
/Span <>BDC
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9 0 0 9 251.52011 452.9138 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 251.5238 452.9138 Tm
[(19 diagnosed 21 days before)30.1 ( )]TJ
0.117 Tw -3.879 -1.222 Td
(stool was collected. Hispanic ethnicity)Tj
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23.12517 41.48 Td
( )Tj
0.498 Tw -18.01017 -1.222 Td
[(was )0.6 (associated )0.5 (with )0.5 (stool )0.5 (positivity)29.7 ( )]TJ
0.246 Tw T*
[(\(61.5% in positive samples vs 23.4%)30.1 ( )]TJ
0.545 Tw T*
(in negative samples, p=0.006 \()Tj
/T1_5 1 Tf
0 Tc 0 Tw (\037)Tj
/TT0 1 Tf
5.967 0 0 5.967 369.4186 412.9129 Tm
(2)Tj
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[(\))-30 (, )]TJ
0 0 1 rg
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0.03 Tc 0.28799 Tw 2.03 36.651 Td
(table)Tj
ET
BT
/Span <>BDC
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( )Tj
EMC
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(1A)Tj
0 0 0 rg
/GS0 gs
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(\). This study may underesti)Tj
0 Tc 0 Tw (-)Tj
0.03 Tc -0.028 Tw -4.09399 -1.263 Td
[(mate prevalence rates as stool positivity)29.7 ( )]TJ
0 Tw 0 -1.263 TD
(may be lower than respiratory samples.)Tj
1.101 Tw 1 -1.238 Td
[(W)118.7 (e successfully sequenced the)30.1 ( )]TJ
0.14301 Tw -1 -1.238 Td
(SARS-)Tj
ET
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( )Tj
EMC
ET
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[(CoV)67.7 (-)]TJ
ET
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/Span <>BDC
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( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 438.0941 693.7039 Tm
[(2 genome from all positive)30.1 ( )]TJ
0.02 Tw -5.211 -1.263 Td
(samples \(full methods in online supple)Tj
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19.70697 30.386 Td
(-)Tj
0.03 Tc 0.306 Tw -17.67597 -1.263 Td
(mental data\), with variant identifica)Tj
0 Tc 0 Tw (-)Tj
0.03 Tc 0.175 Tw T*
[(tion achieved for five samples \(online)30.1 ( )]TJ
-0.007 Tw T*
[(supplemental figure 1B\). W)118.7 (e performed)29.8 ( )]TJ
0.502 Tw T*
[(V4 16S rRNA gene sequencing on)29.8 ( )]TJ
0.235 Tw T*
[(samples )0.5 (using )0.5 (D)35.7 (AD)35.7 (A2 )0.5 (and )0.5 (the )0.5 (SIL)100.8 (V)81.4 (A)30 ( )]TJ
0.536 Tw T*
[(database for microbiome tax)22.1 (onomic)30.1 ( )]TJ
1.015 Tw T*
[(profiling. W)118.6 (e compared microbi)]TJ
0 Tc 0 Tw (-)Tj
0.03 Tc 0.189 Tw T*
[(omes using a 1:2 case\226control match,)30.1 ( )]TJ
0.269 Tw T*
[(controlled for ethnicity)114.5 (, age, delivery)29.8 ( )]TJ
0.617 Tw T*
[(mode, )0.5 (gestational )0.5 (age, )0.5 (gender )0.5 (and)29.9 ( )]TJ
0.062 Tw T*
(recent antibiotic use \()Tj
0 0 1 rg
/GS1 gs
(table)Tj
ET
BT
/Span <>BDC
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( )Tj
EMC
ET
BT
/TT0 1 Tf
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(1B)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 372.9161 408.8629 Tm
15.95195 16.493 Td
(\). Differ)Tj
0 Tc 0 Tw 3.75605 0 Td
(-)Tj
0.03 Tc 0.38499 Tw -17.677 -1.263 Td
[(ential )0.7 (species )0.7 (abundance )0.8 (testing )0.7 (was)29.9 ( )]TJ
0.397 Tw T*
[(performed using DESeq2 contrasting)29.9 ( )]TJ
0.256 Tw T*
(the SARS-)Tj
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 434.80901 523.1989 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 434.8091 523.1989 Tm
[(CoV)67.7 (-)]TJ
ET
BT
/Span <>BDC
/TT0 1 Tf
9 0 0 9 456.1148 523.1989 Tm
( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 456.1211 523.1989 Tm
[(2 positive and control)30.2 ( )]TJ
0.70399 Tw -7.213 -1.263 Td
(samples. W)Tj
9 0 0 9 372.9161 408.8629 Tm
7.80428 11.441 Td
[(e found a significantly)29.8 ( )]TJ
0.42599 Tw -5.77228 -1.263 Td
[(different )0.5 (relative abundance of )0.5 (taxa)30.2 ( )]TJ
1.03 Tw T*
[(\(adjusted p<0.05\) )0.5 (between posi)]TJ
0 Tc 0 Tw (-)Tj
0.03 Tc 0.33099 Tw T*
[(tive )0.5 (and )0.6 (control )0.6 (samples )0.5 (\(all )0.5 (signifi)]TJ
0 Tc 0 Tw (-)Tj
0.03 Tc 0.15199 Tw T*
[(cantly different taxa at a species level)30.2 ( )]TJ
0.095 Tw T*
(shown in )Tj
0 0 1 rg
/GS1 gs
(figure)Tj
ET
BT
/Span <>BDC
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( )Tj
EMC
ET
BT
/TT0 1 Tf
9 0 0 9 460.77392 454.9969 Tm
(1)Tj
0 0 0 rg
/GS0 gs
9 0 0 9 372.9161 408.8629 Tm
10.34798 5.126 Td
[(\). Notably)114.6 (, we found)29.8 ( )]TJ
0.74699 Tw -8.31598 -1.263 Td
(a decreased abundance of )Tj
/TT1 1 Tf
-0.03 Tw (Bifido)Tj
0 Tc 0 Tw (-)Tj
0.03 Tc 0.52699 Tw T*
(bacterium bifidum)Tj
/TT0 1 Tf
( and )Tj
/TT1 1 Tf
-0.03 Tw [(Akker)-18.5 (mansia)29.8 ( )]TJ
T*
(muciniphila)Tj
/TT0 1 Tf
-0.049 Tw [( in positive samples, both of)30.1 ( )]TJ
0.127 Tw T*
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