%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Marie Fisk, Joseph Cheriyan, Divya Mohan, Julia Forman, Kaisa M. Mäki-Petäjä, Carmel M. McEniery, Jonathan Fuld, James H. F. Rudd, Nicholas S. Hopkinson, David A. Lomas, John R. Cockcroft, Ruth Tal-Singer, Michael I. Polkey, Ian B. Wilkinson
The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 14 0 R/Contents 15 0 R/TrimBox[0 0 612 792]>>
endobj
14 0 obj
[16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R 26 0 R]
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref001)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref002)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref002)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref003)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref004)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref005)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref006)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref007)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref008)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref009)>>
endobj
26 0 obj
<>/Border[0 0 0]/A 27 0 R>>
endobj
27 0 obj
<>
endobj
15 0 obj
[28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R]
endobj
28 0 obj
<>stream
q
0.45 0.36 0.35 0.01 k
0 w
575.9997 478.076 m
199.9998 478.076 l
199.9998 478.5761 l
575.9997 478.5761 l
f*
0.83 0.64 0.02 0 k
405.6945 380.9197 m
410.4567 380.9197 l
h
f*
353.9339 302.9102 m
358.6961 302.9102 l
h
f*
281.7638 276.9449 m
286.4693 276.9449 l
h
f*
295.4835 276.9449 m
300.2457 276.9449 l
h
f*
532.5732 211.9181 m
537.3354 211.9181 l
h
f*
539.2063 198.9354 m
543.9685 198.9354 l
h
f*
459.4394 185.8961 m
464.2016 185.8961 l
h
f*
203.4142 159.9307 m
208.1764 159.9307 l
h
f*
544.3087 120.926 m
549.0709 120.926 l
h
f*
562.9606 94.9039 m
567.7228 94.9039 l
h
f*
0 g
1 j
1 J
9.5 0 0 9.5 200.0125 707.7543 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(dose)Tj
ET
Q
q
1 j
1 J
0 w
7.1248 0 0 6.3325 222.4629 711.9496 cm
BT
/F0 1 Tf
1 TL
-0.0056 Tc
0 0 Td
(18)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 230.2299 707.7543 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(F-Fluorodeoxygluc)Tj
8.1935 0 Td
(ose)Tj
1.8142 0 Td
(positron)Tj
3.7298 0 Td
(emission)Tj
4.1177 0 Td
(tomography)Tj
5.4484 0 Td
(co-registered)Tj
5.9856 0 Td
(with)Tj
1.9813 0 Td
(computed)Tj
-34.4512 -1.474 Td
(tomography)Tj
5.4424 0 Td
(\(FDG)Tj
2.6556 0 Td
(PET/CT\))Tj
4.0938 0 Td
(imaging)Tj
3.6761 0 Td
(of)Tj
1.0443 0 Td
(the)Tj
1.5934 0 Td
(aorta)Tj
2.4766 0 Td
(and)Tj
1.8678 0 Td
(carotid)Tj
3.1808 0 Td
(arteries)Tj
3.515 0 Td
(was)Tj
1.9812 0 Td
(performed)Tj
4.7324 0 Td
(to)Tj
-36.2594 -1.474 Td
(quantify)Tj
3.6819 0 Td
(arterial)Tj
3.2285 0 Td
(inflammation,)Tj
6.1049 0 Td
(defined)Tj
3.4553 0 Td
(by)Tj
1.2652 0 Td
(the)Tj
1.5933 0 Td
(tissue-to-blood)Tj
6.7017 0 Td
(ratio)Tj
2.1364 0 Td
(\(TBR\))Tj
2.8705 0 Td
(from)Tj
2.208 0 Td
(scan)Tj
2.3095 0 Td
(images.)Tj
-35.5552 -1.474 Td
(Endothelial)Tj
5.0963 0 Td
(function)Tj
3.682 0 Td
(was)Tj
1.9813 0 Td
(assessed)Tj
4.3981 0 Td
(by)Tj
1.2652 0 Td
(brachial)Tj
3.6701 0 Td
(artery)Tj
2.7511 0 Td
(flow-mediat)Tj
5.0605 0 Td
(ed)Tj
1.3129 0 Td
(dilatation)Tj
4.1655 0 Td
(\(FMD\).)Tj
ET
Q
q
1 j
1 J
0 w
11.4998 0 0 11.4998 200.0125 637.6251 cm
BT
/F2 1 Tf
1 TL
-0.0035 Tc
0 0 Td
(Results)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 200.0125 620.674 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(We)Tj
1.7067 0 Td
(screened)Tj
4.2788 0 Td
(160)Tj
1.8559 0 Td
(patients,)Tj
3.9506 0 Td
(of)Tj
1.0384 0 Td
(whom,)Tj
3.133 0 Td
(36)Tj
1.3069 0 Td
(and)Tj
1.862 0 Td
(37)Tj
1.3069 0 Td
(were)Tj
2.3572 0 Td
(randomised)Tj
5.3709 0 Td
(to)Tj
1.0384 0 Td
(losmapimod)Tj
5.5439 0 Td
(or)Tj
1.0921 0 Td
(placebo.)Tj
-35.8417 -1.474 Td
(The)Tj
1.9275 0 Td
(treatment)Tj
4.4101 0 Td
(effect)Tj
2.6437 0 Td
(of)Tj
1.0443 0 Td
(losmapimod)Tj
5.5499 0 Td
(compared)Tj
4.625 0 Td
(to)Tj
1.0443 0 Td
(placebo)Tj
3.6761 0 Td
(was)Tj
1.9812 0 Td
(not)Tj
1.5934 0 Td
(significant,)Tj
4.8875 0 Td
(at)Tj
1.0444 0 Td
(-0)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(05)Tj
2.4646 0 Td
(for)Tj
-36.892 -1.474 Td
(TBR)Tj
2.208 0 Td
(\(95%)Tj
2.5303 0 Td
(CI:)Tj
1.4919 0 Td
(-0)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(17,)Tj
2.7451 0 Td
(0)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(07\),)Tj
2.7451 0 Td
(p)Tj
0.7639 0 Td
(=)Tj
0.8056 0 Td
(0)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(42,)Tj
2.411 0 Td
(and)Tj
1.8678 0 Td
(+0)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(40%)Tj
3.5985 0 Td
(for)Tj
1.3786 0 Td
(FMD)Tj
2.3751 0 Td
(\(95%)Tj
2.5303 0 Td
(CI:)Tj
1.4919 0 Td
(-1)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(66,)Tj
2.7451 0 Td
(2)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(47\),)Tj
2.7451 0 Td
(p)Tj
0.7639 0 Td
(=)Tj
0.7996 0 Td
(0)Tj
/F6 1 Tf
0 Tc
()Tj
/F0 1 Tf
-0.0042 Tc
(70.)Tj
-35.9968 -1.474 Td
(The)Tj
1.9275 0 Td
(frequency)Tj
4.5653 0 Td
(of)Tj
1.0443 0 Td
(adverse)Tj
3.7358 0 Td
(events)Tj
3.1389 0 Td
(reported)Tj
3.9029 0 Td
(was)Tj
1.9812 0 Td
(similar)Tj
3.0674 0 Td
(in)Tj
0.9847 0 Td
(both)Tj
2.1424 0 Td
(treatment)Tj
4.4101 0 Td
(groups.)Tj
ET
Q
q
1 j
1 J
0 w
11.4998 0 0 11.4998 200.0125 550.6015 cm
BT
/F2 1 Tf
1 TL
-0.0035 Tc
0 0 Td
(Conclusions)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 200.0125 533.5937 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(In)Tj
1.0443 0 Td
(this)Tj
1.7604 0 Td
(plasma)Tj
3.4076 0 Td
(fibrinogen-enriche)Tj
7.8952 0 Td
(d)Tj
0.7638 0 Td
(study,)Tj
2.8705 0 Td
(losmapimod)Tj
5.5499 0 Td
(had)Tj
1.8619 0 Td
(no)Tj
1.3189 0 Td
(effect)Tj
2.6496 0 Td
(on)Tj
1.3129 0 Td
(arterial)Tj
3.2345 0 Td
(inflammation)Tj
-33.6695 -1.474 Td
(and)Tj
1.8619 0 Td
(endothelia)Tj
4.5533 0 Td
(l)Tj
0.4356 0 Td
(function)Tj
3.6761 0 Td
(at)Tj
1.0503 0 Td
(16)Tj
1.3129 0 Td
(weeks)Tj
3.0316 0 Td
(of)Tj
1.0443 0 Td
(treatment,)Tj
4.6846 0 Td
(although)Tj
4.0043 0 Td
(it)Tj
0.7102 0 Td
(was)Tj
1.9812 0 Td
(well)Tj
1.9156 0 Td
(tolerated)Tj
4.064 0 Td
(with)Tj
1.9753 0 Td
(no)Tj
1.3188 0 Td
(sig-)Tj
-37.62 -1.474 Td
(nificant)Tj
3.3478 0 Td
(safety)Tj
2.8645 0 Td
(concerns.)Tj
4.5115 0 Td
(These)Tj
2.9719 0 Td
(findings)Tj
3.6224 0 Td
(do)Tj
1.3129 0 Td
(not)Tj
1.5993 0 Td
(support)Tj
3.515 0 Td
(the)Tj
1.5993 0 Td
(concept)Tj
3.682 0 Td
(that)Tj
1.8739 0 Td
(losmapimod)Tj
5.5499 0 Td
(is)Tj
0.9309 0 Td
(an)Tj
-37.3813 -1.474 Td
(effective)Tj
3.9028 0 Td
(treatment)Tj
4.4101 0 Td
(for)Tj
1.3726 0 Td
(the)Tj
1.5993 0 Td
(adverse)Tj
3.7357 0 Td
(cardiovascular)Tj
6.5883 0 Td
(manifestations)Tj
6.6003 0 Td
(of)Tj
1.0443 0 Td
(COPD.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 425.0267 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 408.0188 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Chronic)Tj
3.5262 0 Td
(Obstructive)Tj
4.8983 0 Td
(Pulmonary)Tj
4.6884 0 Td
(Disease)Tj
3.2258 0 Td
(\(COPD\))Tj
3.6057 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.6519 0 Td
(complex)Tj
3.6227 0 Td
(condition,)Tj
4.3426 0 Td
(which)Tj
2.6476 0 Td
(is)Tj
0.8504 0 Td
(associated)Tj
-32.91 -1.3039 Td
(with)Tj
1.9955 0 Td
(extra-pulmonary)Tj
6.9902 0 Td
(manifestations,)Tj
6.2986 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(systemic)Tj
3.6283 0 Td
(inflammation)Tj
5.6976 0 Td
(and)Tj
1.7291 0 Td
(cardiovascular)Tj
6.0038 0 Td
(dis-)Tj
-35.4215 -1.2982 Td
(ease,)Tj
2.0862 0 Td
(that)Tj
1.7802 0 Td
(increase)Tj
3.4696 0 Td
(patient)Tj
3.0103 0 Td
(morbidity)Tj
4.235 0 Td
(and)Tj
1.7348 0 Td
(mortality)Tj
3.9174 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(].)Tj
1.5988 0 Td
(Current)Tj
3.4242 0 Td
(pharmacological)Tj
6.8428 0 Td
(treatments)Tj
-32.0993 -1.2983 Td
(for)Tj
1.3832 0 Td
(COPD)Tj
2.9254 0 Td
(are)Tj
1.4513 0 Td
(generally)Tj
3.8324 0 Td
(limited)Tj
3.0671 0 Td
(to)Tj
1.0261 0 Td
(inhaled)Tj
3.1975 0 Td
(bronchodilators)Tj
6.6217 0 Td
(and)Tj
1.7348 0 Td
(corticosteroids,)Tj
6.3552 0 Td
(which)Tj
2.6532 0 Td
(do)Tj
1.2529 0 Td
(not)Tj
-35.5008 -1.3039 Td
(address)Tj
3.2258 0 Td
(extra-pulmonary)Tj
6.9901 0 Td
(features.)Tj
3.5717 0 Td
(Diversifying)Tj
5.125 0 Td
(therapeutic)Tj
4.7338 0 Td
(options)Tj
3.2258 0 Td
(to)Tj
1.0205 0 Td
(focus)Tj
2.3301 0 Td
(on)Tj
1.2755 0 Td
(systemic)Tj
3.6284 0 Td
(mani-)Tj
-35.1267 -1.2983 Td
(festations,)Tj
4.2292 0 Td
(and)Tj
1.7291 0 Td
(by)Tj
1.1849 0 Td
(implication)Tj
4.8132 0 Td
(more)Tj
2.3414 0 Td
(accurate)Tj
3.5603 0 Td
(stratification)Tj
5.2781 0 Td
(of)Tj
1.0204 0 Td
(COPD)Tj
2.9197 0 Td
(patients)Tj
3.3732 0 Td
(for)Tj
1.3833 0 Td
(such)Tj
2.058 0 Td
(treat-)Tj
-33.8908 -1.2982 Td
(ments,)Tj
2.8969 0 Td
(might)Tj
2.5966 0 Td
(improve)Tj
3.5829 0 Td
(clinical)Tj
3.0728 0 Td
(outcomes.)Tj
-10.953 -1.2983 Td
(p38)Tj
1.6894 0 Td
(mitogen-activated)Tj
7.4607 0 Td
(protein)Tj
3.1578 0 Td
(kinases)Tj
3.1068 0 Td
(\(MAPK\))Tj
3.7133 0 Td
(are)Tj
1.4457 0 Td
(signalling)Tj
4.0705 0 Td
(molecules)Tj
4.2009 0 Td
(that)Tj
1.7745 0 Td
(regulate)Tj
3.4129 0 Td
(cellu-)Tj
-35.2287 -1.3039 Td
(lar)Tj
1.2699 0 Td
(responses)Tj
4.0932 0 Td
(to)Tj
1.0261 0 Td
(extra-cellular)Tj
5.4822 0 Td
(stresses)Tj
3.1804 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(].)Tj
1.5988 0 Td
(They)Tj
2.2393 0 Td
(also)Tj
1.7688 0 Td
(regulate)Tj
3.4072 0 Td
(pro-inflammatory)Tj
7.4551 0 Td
(cytokines,)Tj
4.2293 0 Td
(and)Tj
-35.7503 -1.2983 Td
(have)Tj
2.0579 0 Td
(a)Tj
0.652 0 Td
(key)Tj
1.5987 0 Td
(role)Tj
1.7688 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(initiation)Tj
3.9231 0 Td
(and)Tj
1.7292 0 Td
(development)Tj
5.4084 0 Td
(of)Tj
1.0148 0 Td
(inflammatory)Tj
5.709 0 Td
(diseases,)Tj
3.6056 0 Td
(including)Tj
4.0422 0 Td
(COPD)Tj
-34.0155 -1.2983 Td
(and)Tj
1.7291 0 Td
(atherosclerosis)Tj
6.1058 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(])Tj
1.3719 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(].)Tj
1.6044 0 Td
(Therefore,)Tj
4.388 0 Td
(pharmacological)Tj
6.8428 0 Td
(inhibition)Tj
4.2293 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(p38)Tj
1.6895 0 Td
(MAPK)Tj
3.0273 0 Td
(pathway,)Tj
-33.4712 -1.3039 Td
(may)Tj
1.9275 0 Td
(represent)Tj
3.9571 0 Td
(a)Tj
0.652 0 Td
(potential)Tj
3.7644 0 Td
(novel)Tj
2.3981 0 Td
(approach)Tj
3.9515 0 Td
(to)Tj
1.0261 0 Td
(treating)Tj
3.3278 0 Td
(the)Tj
1.4684 0 Td
(adverse)Tj
3.2144 0 Td
(cardiovascular)Tj
6.0038 0 Td
(manifestations)Tj
-31.6911 -1.2982 Td
(of)Tj
1.0147 0 Td
(COPD.)Tj
3.1522 0 Td
(To)Tj
1.3379 0 Td
(date,)Tj
2.126 0 Td
(losmapimod)Tj
5.227 0 Td
(\(GW856553)Tj
5.0967 0 Td
(Brentford)Tj
4.1329 0 Td
(UK\),)Tj
2.194 0 Td
(a)Tj
0.6576 0 Td
(selective)Tj
3.5376 0 Td
(p38)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
(/)Tj
/F11 1 Tf
()Tj
/F7 1 Tf
3.0784 0 Td
(MAPK)Tj
3.0274 0 Td
(inhibi-)Tj
-34.5824 -1.2983 Td
(tor)Tj
1.3889 0 Td
(has)Tj
1.5364 0 Td
(been)Tj
2.1203 0 Td
(evaluated)Tj
3.9798 0 Td
(as)Tj
1.0091 0 Td
(an)Tj
1.1962 0 Td
(anti-inflammatory)Tj
7.6025 0 Td
(therapy)Tj
3.2428 0 Td
(in)Tj
1.0318 0 Td
(different)Tj
3.651 0 Td
(patient)Tj
2.9991 0 Td
(populations)Tj
4.9436 0 Td
(includ-)Tj
-34.7015 -1.3039 Td
(ing)Tj
1.5023 0 Td
(COPD)Tj
2.9253 0 Td
(and)Tj
1.7292 0 Td
(cardiovascular)Tj
6.0037 0 Td
(disease.)Tj
3.2428 0 Td
(In)Tj
1.1055 0 Td
(COPD,)Tj
3.1521 0 Td
(losmapimod)Tj
5.2271 0 Td
(reduces)Tj
3.2768 0 Td
(acute)Tj
2.3301 0 Td
(phase)Tj
2.4831 0 Td
(circulating)Tj
-32.978 -1.2983 Td
(proteins)Tj
3.5149 0 Td
(such)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(fibrinogen,)Tj
4.6375 0 Td
(and)Tj
1.7291 0 Td
(a)Tj
0.6576 0 Td
(reduction)Tj
4.1159 0 Td
(in)Tj
1.0318 0 Td
(hyperinflation)Tj
5.9187 0 Td
(have)Tj
2.0636 0 Td
(been)Tj
2.1203 0 Td
(described)Tj
4.0535 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(].)Tj
1.5988 0 Td
(In)Tj
1.1112 0 Td
(car-)Tj
-35.6256 -1.2982 Td
(diovascular)Tj
4.7735 0 Td
(disease,)Tj
3.2428 0 Td
(losmapimod)Tj
5.227 0 Td
(attenuated)Tj
4.4334 0 Td
(arterial)Tj
3.0671 0 Td
(inflammation)Tj
5.6976 0 Td
(in)Tj
1.0318 0 Td
(atherosclerosis)Tj
6.1058 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(],)Tj
-33.579 -1.304 Td
(improved)Tj
4.1045 0 Td
(endothelial)Tj
4.6715 0 Td
(function)Tj
3.6283 0 Td
(in)Tj
1.0375 0 Td
(hypercholesterolemic)Tj
8.7816 0 Td
(subjects)Tj
3.3789 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(],)Tj
1.6044 0 Td
(and)Tj
1.7291 0 Td
(showed)Tj
3.2485 0 Td
(a)Tj
0.6576 0 Td
(trend)Tj
-32.8419 -1.2982 Td
(towards)Tj
3.4015 0 Td
(improved)Tj
4.1102 0 Td
(left)Tj
1.474 0 Td
(ventricular)Tj
4.5864 0 Td
(function)Tj
3.6284 0 Td
(following)Tj
3.9798 0 Td
(non-ST)Tj
3.2598 0 Td
(elevation)Tj
3.8268 0 Td
(myocardial)Tj
4.7054 0 Td
(infarction)Tj
-32.9723 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(].)Tj
1.1962 -1.2983 Td
(Arterial)Tj
3.3165 0 Td
(inflammation,)Tj
5.9243 0 Td
(measured)Tj
4.1103 0 Td
(by)Tj
1.1792 0 Td
(positron)Tj
3.5999 0 Td
(emission)Tj
3.7758 0 Td
(tomography)Tj
5.1193 0 Td
(\(PET\))Tj
2.6419 0 Td
(imaging,)Tj
3.7133 0 Td
(is)Tj
0.8448 0 Td
(a)Tj
-35.4215 -1.3039 Td
(promising)Tj
4.3426 0 Td
(vascular)Tj
3.4753 0 Td
(biomarker,)Tj
4.6374 0 Td
(which)Tj
2.6532 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.1203 0 Td
(shown)Tj
2.8516 0 Td
(to)Tj
1.0261 0 Td
(improve)Tj
3.5773 0 Td
(prediction)Tj
4.371 0 Td
(of)Tj
1.0148 0 Td
(cardiovascular)Tj
-31.6117 -1.2982 Td
(events)Tj
2.7269 0 Td
(beyond)Tj
3.1918 0 Td
(traditional)Tj
4.4163 0 Td
(risk)Tj
1.7178 0 Td
(factors,)Tj
3.1294 0 Td
(and)Tj
1.7291 0 Td
(also)Tj
1.7688 0 Td
(informed)Tj
3.9742 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4683 0 Td
(timing)Tj
2.8857 0 Td
(of)Tj
1.0148 0 Td
(such)Tj
2.0579 0 Td
(events)Tj
2.7326 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
1.5987 0 Td
(Bra-)Tj
-35.6879 -1.2983 Td
(chial)Tj
2.1089 0 Td
(artery)Tj
2.5625 0 Td
(flow-mediated)Tj
6.0094 0 Td
(dilatation)Tj
4.0365 0 Td
(\(FMD\))Tj
3.0444 0 Td
(is)Tj
0.8391 0 Td
(a)Tj
0.6463 0 Td
(measure)Tj
3.5716 0 Td
(of)Tj
1.0035 0 Td
(endothelial)Tj
4.6601 0 Td
(function)Tj
3.6226 0 Td
(which)Tj
2.6362 0 Td
(is)Tj
0.8391 0 Td
(asso-)Tj
-35.5802 -1.3039 Td
(ciated)Tj
2.5908 0 Td
(with)Tj
2.0012 0 Td
(cardiovascular)Tj
6.0038 0 Td
(outcomes,)Tj
4.3086 0 Td
(and)Tj
1.7291 0 Td
(has)Tj
1.5478 0 Td
(prognostic)Tj
4.4843 0 Td
(value)Tj
2.3074 0 Td
(in)Tj
1.0318 0 Td
(different)Tj
3.6567 0 Td
(clinical)Tj
3.0784 0 Td
(cohorts)Tj
3.2145 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
-35.9544 -1.2983 Td
(COPD)Tj
2.9253 0 Td
(patients)Tj
3.3675 0 Td
(have)Tj
2.058 0 Td
(increased)Tj
4.0025 0 Td
(arterial)Tj
3.067 0 Td
(inflammation)Tj
5.6976 0 Td
(compared)Tj
4.2406 0 Td
(to)Tj
1.0262 0 Td
(healthy)Tj
3.1351 0 Td
(controls,)Tj
3.7077 0 Td
(regardless)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 377.6881 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(p38)Tj
1.8567 0 Td
(mitogen)Tj
3.7134 0 Td
(activated)Tj
4.1528 0 Td
(protein)Tj
3.2173 0 Td
(kinase)Tj
3.0544 0 Td
(inhibition)Tj
4.0748 0 Td
(and)Tj
1.8567 0 Td
(COPD)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01941)Tj
4.089 0 Td
(97)Tj
0 g
2.0906 0 Td
(March)Tj
2.9622 0 Td
(22,)Tj
1.5874 0 Td
(2018)Tj
34.3562 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(17)Tj
/F9 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(6118\))Tj
2.4236 0 Td
(\(as)Tj
1.3677 0 Td
(a)Tj
0.6378 0 Td
(component)Tj
4.4434 0 Td
(study)Tj
2.2677 0 Td
(of)Tj
0.9425 0 Td
(the)Tj
1.3748 0 Td
(ERICA)Tj
-13.4575 -1.3748 Td
(\(Evaluation)Tj
4.3299 0 Td
(of)Tj
0.9425 0 Td
(the)Tj
1.3748 0 Td
(Role)Tj
1.8922 0 Td
(of)Tj
0.9496 0 Td
(Inflammation)Tj
5.1449 0 Td
(in)Tj
0.8859 0 Td
(Chronic)Tj
-15.5198 -1.3749 Td
(Airways)Tj
3.1464 0 Td
(Disease\))Tj
3.4158 0 Td
(Collaboration,)Tj
5.3221 0 Td
(which)Tj
2.4236 0 Td
(includes)Tj
-14.3079 -1.3748 Td
(academic)Tj
3.7488 0 Td
(partners)Tj
3.3024 0 Td
(and)Tj
1.5874 0 Td
(GSK.)Tj
2.0835 0 Td
(GSK)Tj
1.8567 0 Td
(made)Tj
-12.5788 -1.3748 Td
(contributio)Tj
3.9897 0 Td
(ns)Tj
1.1197 0 Td
(towards)Tj
3.2103 0 Td
(study)Tj
2.2677 0 Td
(managem)Tj
3.7135 0 Td
(ent)Tj
1.3748 0 Td
(and)Tj
-15.6757 -1.3748 Td
(provision)Tj
3.6496 0 Td
(of)Tj
0.9496 0 Td
(study)Tj
2.2677 0 Td
(drug.)Tj
2.1686 0 Td
(JC,)Tj
1.3889 0 Td
(CMM)Tj
2.2536 0 Td
(and)Tj
1.5874 0 Td
(IBW)Tj
-14.2654 -1.3748 Td
(acknowledge)Tj
5.0527 0 Td
(funding)Tj
3.0331 0 Td
(support)Tj
3.104 0 Td
(from)Tj
2.0055 0 Td
(the)Tj
1.3748 0 Td
(NIHR)Tj
-14.5701 -1.3748 Td
(Cambridge)Tj
4.2661 0 Td
(Compre)Tj
2.9481 0 Td
(hensive)Tj
3.0472 0 Td
(Biomedical)Tj
4.2946 0 Td
(Researc)Tj
2.9976 0 Td
(h)Tj
-17.5536 -1.3748 Td
(Centre.)Tj
2.8488 0 Td
(This)Tj
1.7787 0 Td
(work)Tj
2.0623 0 Td
(was)Tj
1.7008 0 Td
(supported)Tj
3.9968 0 Td
(by)Tj
1.1127 0 Td
(the)Tj
1.3748 0 Td
(NIHR)Tj
-14.8749 -1.3748 Td
(Respiratory)Tj
4.5 0 Td
(Disease)Tj
3.111 0 Td
(Biomedical)Tj
4.2875 0 Td
(Research)Tj
3.6992 0 Td
(Unit)Tj
1.7292 0 Td
(at)Tj
-17.3269 -1.3749 Td
(the)Tj
1.3677 0 Td
(Royal)Tj
2.3173 0 Td
(Brompton)Tj
3.9544 0 Td
(and)Tj
1.5945 0 Td
(Harefield)Tj
3.4937 0 Td
(NHS)Tj
1.9205 0 Td
(Foundation)Tj
-14.6481 -1.3748 Td
(Trust)Tj
2.1543 0 Td
(and)Tj
1.5874 0 Td
(Imperia)Tj
2.8205 0 Td
(l)Tj
0.4181 0 Td
(College)Tj
2.9197 0 Td
(London)Tj
3.0615 0 Td
(who)Tj
1.8071 0 Td
(part)Tj
1.6724 0 Td
(fund)Tj
-16.441 -1.3748 Td
(MIP's)Tj
2.3669 0 Td
(salary.)Tj
2.6292 0 Td
(The)Tj
1.5945 0 Td
(views)Tj
2.3173 0 Td
(expressed)Tj
3.9969 0 Td
(in)Tj
0.8858 0 Td
(this)Tj
-13.7906 -1.3748 Td
(publication)Tj
4.2661 0 Td
(are)Tj
1.3678 0 Td
(those)Tj
2.2677 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(authors)Tj
3.0473 0 Td
(and)Tj
1.5874 0 Td
(not)Tj
-14.8536 -1.3748 Td
(necessaril)Tj
3.6921 0 Td
(y)Tj
0.6449 0 Td
(those)Tj
2.2677 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3678 0 Td
(NHS,)Tj
2.1472 0 Td
(The)Tj
1.5874 0 Td
(Nationa)Tj
2.8205 0 Td
(l)Tj
0.4182 0 Td
(Institute)Tj
-15.8954 -1.3748 Td
(for)Tj
1.2543 0 Td
(Health)Tj
2.5725 0 Td
(Research)Tj
3.6992 0 Td
(or)Tj
0.9992 0 Td
(the)Tj
1.3677 0 Td
(Department)Tj
4.5922 0 Td
(of)Tj
0.9496 0 Td
(Health.)Tj
-15.4347 -1.3748 Td
(The)Tj
1.5874 0 Td
(funders)Tj
3.0472 0 Td
(had)Tj
1.5874 0 Td
(no)Tj
1.1693 0 Td
(role)Tj
1.6158 0 Td
(in)Tj
0.8858 0 Td
(study)Tj
2.2607 0 Td
(design,)Tj
2.9055 0 Td
(data)Tj
-15.0591 -1.3749 Td
(collection)Tj
3.7417 0 Td
(and)Tj
1.5874 0 Td
(analysis)Tj
2.9623 0 Td
(,)Tj
0.4464 0 Td
(decision)Tj
3.2882 0 Td
(to)Tj
0.9496 0 Td
(publish,)Tj
3.1465 0 Td
(or)Tj
-16.1221 -1.3819 Td
(preparation)Tj
4.4433 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(manuscript.)Tj
/F8 1 Tf
-6.7606 -2.1189 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F9 1 Tf
0.4819 0 Td
(JRF,)Tj
1.8709 0 Td
(KMP,)Tj
2.2465 0 Td
(CMM,)Tj
2.4803 0 Td
(JHRF)Tj
2.2394 0 Td
(and)Tj
-17.0292 -1.3748 Td
(NSH)Tj
1.9204 0 Td
(have)Tj
1.956 0 Td
(no)Tj
1.1693 0 Td
(disclosures)Tj
4.4433 0 Td
(to)Tj
0.9425 0 Td
(declare.)Tj
3.104 0 Td
(MF)Tj
1.3961 0 Td
(and)Tj
1.5874 0 Td
(IBW)Tj
-16.519 -1.3748 Td
(received)Tj
3.3023 0 Td
(an)Tj
1.1126 0 Td
(imaging)Tj
3.2032 0 Td
(award)Tj
2.4804 0 Td
(from)Tj
2.0126 0 Td
(GSK)Tj
1.8567 0 Td
(during)Tj
2.615 0 Td
(the)Tj
-16.5828 -1.3748 Td
(course)Tj
2.7354 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3748 0 Td
(study.)Tj
2.4875 0 Td
(JC)Tj
1.1693 0 Td
(is)Tj
0.8291 0 Td
(employed)Tj
3.8551 0 Td
(by)Tj
1.1127 0 Td
(Cambridge)Tj
-14.5135 -1.3748 Td
(University)Tj
3.9189 0 Td
(Hospita)Tj
2.8205 0 Td
(ls)Tj
0.8362 0 Td
(NHS)Tj
1.9205 0 Td
(Foundation)Tj
4.3512 0 Td
(Trust)Tj
2.1544 0 Td
(and)Tj
1.5874 0 Td
(is)Tj
-17.5891 -1.3819 Td
(obligated)Tj
3.6 0 Td
(to)Tj
0.9496 0 Td
(spend)Tj
2.4803 0 Td
(50%)Tj
1.9701 0 Td
(of)Tj
0.9496 0 Td
(his)Tj
1.3111 0 Td
(time)Tj
1.8425 0 Td
(on)Tj
1.1693 0 Td
(GSK)Tj
1.8567 0 Td
(clinical)Tj
-16.1292 -1.3748 Td
(trial)Tj
1.5874 0 Td
(research)Tj
3.4157 0 Td
(via)Tj
1.2615 0 Td
(a)Tj
0.6378 0 Td
(secondment)Tj
4.8118 0 Td
(agreement)Tj
3.9473 0 Td
(,)Tj
-15.6615 -1.3749 Td
(representin)Tj
4.1669 0 Td
(g)Tj
0.6945 0 Td
(a)Tj
0.6449 0 Td
(significa)Tj
3.0402 0 Td
(nt)Tj
0.9496 0 Td
(relationship;)Tj
4.7481 0 Td
(however)Tj
3.1535 0 Td
(,)Tj
0.4465 0 Td
(he)Tj
-17.8442 -1.3748 Td
(receives)Tj
3.2456 0 Td
(no)Tj
1.1693 0 Td
(benefits)Tj
3.1394 0 Td
(or)Tj
0.9993 0 Td
(compen)Tj
3.0118 0 Td
(sation)Tj
2.4591 0 Td
(from)Tj
2.0126 0 Td
(GSK.)Tj
2.0835 0 Td
(JF)Tj
-18.1206 -1.3748 Td
(reports)Tj
2.8771 0 Td
(personal)Tj
3.4087 0 Td
(fees)Tj
1.7363 0 Td
(from)Tj
2.0126 0 Td
(GSK,)Tj
2.0835 0 Td
(outside)Tj
2.9268 0 Td
(the)Tj
-15.045 -1.3748 Td
(submitted)Tj
3.9401 0 Td
(work;)Tj
2.289 0 Td
(MIP)Tj
1.7504 0 Td
(reports)Tj
2.8843 0 Td
(personal)Tj
3.4016 0 Td
(fees)Tj
1.7433 0 Td
(from)Tj
-16.0087 -1.3748 Td
(GSK)Tj
1.8567 0 Td
(during)Tj
2.6149 0 Td
(the)Tj
1.3678 0 Td
(conduct)Tj
3.2173 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3678 0 Td
(study.)Tj
2.4874 0 Td
(JRC)Tj
1.7575 0 Td
(reports)Tj
-15.619 -1.3748 Td
(grants)Tj
2.5724 0 Td
(from)Tj
2.0126 0 Td
(GSK)Tj
1.8567 0 Td
(outside)Tj
2.9268 0 Td
(this)Tj
1.5662 0 Td
(submitted)Tj
3.9402 0 Td
(work.)Tj
2.289 0 Td
(DM)Tj
-17.1639 -1.3748 Td
(and)Tj
1.5874 0 Td
(RT-S)Tj
2.1118 0 Td
(are)Tj
1.3748 0 Td
(employe)Tj
3.1536 0 Td
(es)Tj
1.063 0 Td
(and)Tj
1.5874 0 Td
(shareholders)Tj
5.0315 0 Td
(of)Tj
0.9496 0 Td
(GSK.)Tj
-16.8591 -1.3749 Td
(DAL)Tj
1.8071 0 Td
(reports)Tj
2.8771 0 Td
(grants)Tj
2.5725 0 Td
(from)Tj
2.0126 0 Td
(GlaxoSmi)Tj
3.5646 0 Td
(thKline,)Tj
-12.8339 -1.3748 Td
(personal)Tj
3.4016 0 Td
(fees)Tj
1.7433 0 Td
(from)Tj
2.0126 0 Td
(GSK)Tj
1.8567 0 Td
(and)Tj
1.5874 0 Td
(non-financia)Tj
4.578 0 Td
(l)Tj
0.4181 0 Td
(support)Tj
-15.5977 -1.3748 Td
(from)Tj
2.0126 0 Td
(GSK,)Tj
2.0764 0 Td
(during)Tj
2.6149 0 Td
(the)Tj
1.3749 0 Td
(conduct)Tj
3.2102 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3678 0 Td
(study;)Tj
2.4874 0 Td
(and)Tj
-16.0938 -1.3748 Td
(personal)Tj
3.4016 0 Td
(fees)Tj
1.7433 0 Td
(from)Tj
2.0126 0 Td
(GSK,)Tj
2.0764 0 Td
(grants)Tj
2.5724 0 Td
(from)Tj
2.0127 0 Td
(GSK,)Tj
-13.819 -1.3748 Td
(personal)Tj
3.4016 0 Td
(fees)Tj
1.7433 0 Td
(from)Tj
2.0126 0 Td
(Griffols,)Tj
3.1252 0 Td
(outside)Tj
2.9339 0 Td
(the)Tj
1.3677 0 Td
(submitted)Tj
ET
endstream
endobj
29 0 obj
<>stream
endstream
endobj
30 0 obj
<>stream
endstream
endobj
31 0 obj
<>stream
endstream
endobj
32 0 obj
<>stream
endstream
endobj
33 0 obj
<>stream
endstream
endobj
34 0 obj
<>stream
endstream
endobj
35 0 obj
<>stream
endstream
endobj
36 0 obj
<>stream
endstream
endobj
37 0 obj
<>stream
endstream
endobj
38 0 obj
<>stream
BT
0 31.0892 Td
(work.)Tj
ET
Q
endstream
endobj
39 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 42 0 R/Contents 43 0 R/TrimBox[0 0 612 792]>>
endobj
42 0 obj
[44 0 R 45 0 R 46 0 R 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R 53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R]
endobj
44 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref010)>>
endobj
45 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref011)>>
endobj
46 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref001)>>
endobj
47 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref012)>>
endobj
48 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref013)>>
endobj
49 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref014)>>
endobj
50 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.s001)>>
endobj
51 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref015)>>
endobj
52 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref016)>>
endobj
53 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref017)>>
endobj
54 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref018)>>
endobj
55 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.s005)>>
endobj
56 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.s006)>>
endobj
57 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.s010)>>
endobj
58 0 obj
<>/Border[0 0 0]/A 59 0 R>>
endobj
59 0 obj
<>
endobj
43 0 obj
[60 0 R 61 0 R 62 0 R 63 0 R 64 0 R 65 0 R 66 0 R 67 0 R 68 0 R 69 0 R 70 0 R 71 0 R 72 0 R 73 0 R 74 0 R 75 0 R 76 0 R 77 0 R 78 0 R]
endobj
60 0 obj
<>stream
q
0.83 0.64 0.02 0 k
280.4598 706.337 m
289.9843 706.337 l
h
f*
510.0094 706.337 m
519.5339 706.337 l
h
f*
331.8236 680.315 m
336.5858 680.315 l
h
f*
525.7134 654.3496 m
535.2378 654.3496 l
h
f*
531.6094 628.3276 m
541.0772 628.3276 l
h
f*
0 g
292.5921 614.3811 m
302.8535 614.3811 l
302.8535 613.8709 l
292.5921 613.8709 l
f*
337.663 614.3811 m
342.7654 614.3811 l
342.7654 613.8709 l
337.663 613.8709 l
f*
347.811 614.3811 m
353.1969 614.3811 l
353.1969 613.8709 l
347.811 613.8709 l
f*
471.515 614.3811 m
476.7874 614.3811 l
476.7874 613.8709 l
471.515 613.8709 l
f*
331.4835 601.3417 m
344.7496 601.3417 l
344.7496 600.8882 l
331.4835 600.8882 l
f*
0.83 0.64 0.02 0 k
511.6535 480.8126 m
521.178 480.8126 l
h
f*
225.3543 467.8299 m
271.1622 467.8299 l
h
f*
487.1055 224.9008 m
496.6299 224.9008 l
h
f*
498.9543 172.9134 m
508.422 172.9134 l
h
f*
536.8819 159.9307 m
546.3496 159.9307 l
h
f*
203.4142 133.9087 m
212.9386 133.9087 l
h
f*
352.0063 94.9039 m
361.5307 94.9039 l
h
f*
381.0331 94.9039 m
390.5575 94.9039 l
h
f*
387.326 81.9213 m
411.6472 81.9213 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(of)Tj
1.0147 0 Td
(smoking)Tj
3.6851 0 Td
(history)Tj
3.0047 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(],)Tj
2.0806 0 Td
(and)Tj
1.7291 0 Td
(also)Tj
1.7688 0 Td
(demonstrate)Tj
5.2327 0 Td
(impaired)Tj
3.8438 0 Td
(endothelial)Tj
4.6715 0 Td
(function)Tj
3.6283 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(].)Tj
2.0749 0 Td
(Addition-)Tj
-32.7342 -1.3039 Td
(ally,)Tj
1.8141 0 Td
(systemic)Tj
3.6227 0 Td
(inflammation)Tj
5.6862 0 Td
(is)Tj
0.8391 0 Td
(hypothesised)Tj
5.4028 0 Td
(to)Tj
1.0204 0 Td
(be)Tj
1.1396 0 Td
(a)Tj
0.6406 0 Td
(causal)Tj
2.6362 0 Td
(factor)Tj
2.5342 0 Td
(in)Tj
1.0261 0 Td
(the)Tj
1.457 0 Td
(increased)Tj
3.9911 0 Td
(cardiovascular)Tj
-31.8101 -1.2982 Td
(risk)Tj
1.7121 0 Td
(observed)Tj
3.7984 0 Td
(in)Tj
1.0374 0 Td
(COPD)Tj
2.9254 0 Td
(patients)Tj
3.3675 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(].)Tj
1.5987 0 Td
(Plasma)Tj
3.0728 0 Td
(fibrinogen,)Tj
4.6431 0 Td
(a)Tj
0.652 0 Td
(stable)Tj
2.4888 0 Td
(biomarker)Tj
4.4163 0 Td
(of)Tj
1.0148 0 Td
(systemic)Tj
3.6283 0 Td
(inflam-)Tj
-34.3556 -1.2983 Td
(mation)Tj
3.0954 0 Td
(in)Tj
1.0318 0 Td
(COPD,)Tj
3.1521 0 Td
(is)Tj
0.8504 0 Td
(positively)Tj
4.0138 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
1.9956 0 Td
(cardiovascular)Tj
6.0037 0 Td
(risk)Tj
1.7178 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(general)Tj
3.1295 0 Td
(population,)Tj
-31.7535 -1.2983 Td
(and)Tj
1.7291 0 Td
(is)Tj
0.8504 0 Td
(implicated)Tj
4.4447 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4683 0 Td
(development)Tj
5.4141 0 Td
(of)Tj
1.0148 0 Td
(vascular)Tj
3.4696 0 Td
(dysfunction)Tj
4.972 0 Td
(and)Tj
1.7291 0 Td
(atherosclerosis)Tj
6.1058 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(].)Tj
2.0749 0 Td
(It)Tj
0.8617 0 Td
(has)Tj
-35.1663 -1.3039 Td
(also)Tj
1.7688 0 Td
(recently)Tj
3.4072 0 Td
(been)Tj
2.1203 0 Td
(qualified)Tj
3.7133 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4684 0 Td
(Food)Tj
2.2904 0 Td
(and)Tj
1.7291 0 Td
(Drug)Tj
2.3244 0 Td
(Administration)Tj
6.4176 0 Td
(\(FDA\))Tj
2.8459 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6577 0 Td
(drug)Tj
2.1089 0 Td
(develop-)Tj
-33.046 -1.2982 Td
(ment)Tj
2.3073 0 Td
(tool)Tj
1.7802 0 Td
(for)Tj
1.3833 0 Td
(predicting)Tj
4.3313 0 Td
(the)Tj
1.4683 0 Td
(risk)Tj
1.7178 0 Td
(for)Tj
1.389 0 Td
(COPD)Tj
2.9253 0 Td
(exacerbations,)Tj
5.9074 0 Td
(and)Tj
1.7291 0 Td
(mortality)Tj
3.9175 0 Td
(in)Tj
1.0374 0 Td
(COPD)Tj
2.9254 0 Td
([)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(].)Tj
-31.6231 -1.2983 Td
(The)Tj
1.7858 0 Td
(EVOLUTION)Tj
5.9357 0 Td
(\(Evaluation)Tj
4.8472 0 Td
(of)Tj
1.0148 0 Td
(Losmapimod)Tj
5.5219 0 Td
(in)Tj
1.0374 0 Td
(Chronic)Tj
3.5263 0 Td
(Obstructive)Tj
4.8982 0 Td
(Pulmonary)Tj
4.6885 0 Td
(Disease)Tj
-34.452 -1.3039 Td
(patients)Tj
3.3675 0 Td
(with)Tj
1.9956 0 Td
(systemic)Tj
3.6283 0 Td
(inflammation)Tj
5.6976 0 Td
(stratified)Tj
3.7587 0 Td
(by)Tj
1.1792 0 Td
(fibrinogen\))Tj
4.7565 0 Td
(trial,)Tj
2.0636 0 Td
(was)Tj
1.6951 0 Td
(an)Tj
1.2019 0 Td
(experimental)Tj
5.4595 0 Td
(medi-)Tj
-34.8035 -1.304 Td
(cine)Tj
1.8821 0 Td
(study,)Tj
2.6136 0 Td
(designed)Tj
3.7644 0 Td
(to)Tj
1.0261 0 Td
(test)Tj
1.5987 0 Td
(the)Tj
1.474 0 Td
(hypothesis)Tj
4.4617 0 Td
(that)Tj
1.7802 0 Td
(losmapimod,)Tj
5.4538 0 Td
(as)Tj
1.0148 0 Td
(an)Tj
1.2019 0 Td
(anti-inflammatory)Tj
7.6025 0 Td
(agent,)Tj
-33.8738 -1.2982 Td
(reduces)Tj
3.2768 0 Td
(arterial)Tj
3.067 0 Td
(inflammation)Tj
5.6976 0 Td
(and)Tj
1.7292 0 Td
(concomitantly)Tj
5.998 0 Td
(improves)Tj
3.9402 0 Td
(endothelial)Tj
4.6714 0 Td
(function)Tj
3.6284 0 Td
(\(our)Tj
1.9672 0 Td
(co-)Tj
-33.9758 -1.2983 Td
(primary)Tj
3.4525 0 Td
(endpoints)Tj
4.218 0 Td
(of)Tj
1.0147 0 Td
(the)Tj
1.4741 0 Td
(study\))Tj
2.7269 0 Td
(in)Tj
1.0374 0 Td
(a)Tj
0.652 0 Td
(cohort)Tj
2.8573 0 Td
(of)Tj
1.0148 0 Td
(COPD)Tj
2.9253 0 Td
(patients)Tj
3.3676 0 Td
(with)Tj
1.9956 0 Td
(evidence)Tj
3.7133 0 Td
(of)Tj
1.0148 0 Td
(systemic)Tj
-31.4643 -1.3039 Td
(inflammation,)Tj
5.913 0 Td
(stratified)Tj
3.7474 0 Td
(by)Tj
1.1735 0 Td
(plasma)Tj
3.0217 0 Td
(fibrinogen.)Tj
4.6261 0 Td
(Secondary)Tj
4.3767 0 Td
(endpoints)Tj
4.2122 0 Td
(included)Tj
3.7021 0 Td
(safety)Tj
2.4718 0 Td
(and)Tj
1.7177 0 Td
(tolera-)Tj
-34.9622 -1.2983 Td
(bility)Tj
2.2563 0 Td
(of)Tj
1.0148 0 Td
(losmapimod,)Tj
5.4538 0 Td
(and)Tj
1.7292 0 Td
(the)Tj
1.474 0 Td
(effects)Tj
2.7212 0 Td
(of)Tj
1.0148 0 Td
(losmapimod)Tj
5.2271 0 Td
(on)Tj
1.2755 0 Td
(arterial)Tj
3.0671 0 Td
(stiffness)Tj
3.4186 0 Td
(and)Tj
1.7291 0 Td
(blood)Tj
2.5115 0 Td
(biomarkers)Tj
-32.893 -1.2982 Td
(of)Tj
1.0147 0 Td
(inflammation.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 498.8976 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Materials)Tj
4.5071 0 Td
(and)Tj
1.989 0 Td
(methods)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 481.8897 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(The)Tj
1.7744 0 Td
(EVOLUTION)Tj
5.9301 0 Td
(study)Tj
2.3811 0 Td
(design)Tj
2.8006 0 Td
(and)Tj
1.7234 0 Td
(protocol)Tj
3.5887 0 Td
(have)Tj
2.0522 0 Td
(been)Tj
2.1147 0 Td
(previously)Tj
4.3426 0 Td
(published)Tj
4.1159 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(])Tj
1.8425 0 Td
(and)Tj
1.7235 0 Td
(the)Tj
1.457 0 Td
(pro-)Tj
-35.8467 -1.2982 Td
(tocol)Tj
2.194 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1)Tj
1.5023 0 Td
(Protocol)Tj
0 g
(\))Tj
3.9742 0 Td
(is)Tj
0.839 0 Td
(included)Tj
3.702 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4627 0 Td
(Supporting)Tj
4.7055 0 Td
(Information.)Tj
5.3688 0 Td
(Key)Tj
1.7631 0 Td
(trial)Tj
1.8312 0 Td
(information)Tj
5.0683 0 Td
(is)Tj
0.839 0 Td
(summa-)Tj
-34.2819 -1.2983 Td
(rised)Tj
2.1713 0 Td
(below.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 429.4488 cm
BT
/F12 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Study)Tj
2.6173 0 Td
(design)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 412.4409 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(EVOLUTION)Tj
5.9357 0 Td
(was)Tj
1.7007 0 Td
(a)Tj
0.652 0 Td
(randomised,)Tj
5.2327 0 Td
(double-blind)Tj
5.4085 0 Td
(placebo-controlled,)Tj
7.954 0 Td
(parallel-group,)Tj
6.1057 0 Td
(stratified)Tj
-32.9893 -1.2982 Td
(experimental)Tj
5.4594 0 Td
(medicine)Tj
3.9175 0 Td
(trial,)Tj
2.0636 0 Td
(which)Tj
2.6476 0 Td
(recruited)Tj
3.855 0 Td
(from)Tj
2.2054 0 Td
(two)Tj
1.7121 0 Td
(UK)Tj
1.6271 0 Td
(tertiary)Tj
3.1407 0 Td
(centres)Tj
3.0671 0 Td
(\(Addenbrooke's)Tj
-29.6955 -1.2983 Td
(Hospital,)Tj
3.8437 0 Td
(Cambridge)Tj
4.6998 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(Royal)Tj
2.4831 0 Td
(Brompton)Tj
4.371 0 Td
(Hospital,)Tj
3.8438 0 Td
(London\).)Tj
3.9628 0 Td
(The)Tj
1.7801 0 Td
(study)Tj
2.3924 0 Td
(was)Tj
1.6952 0 Td
(approved)Tj
3.9741 0 Td
(by)Tj
-36.2435 -1.3039 Td
(Cambridge)Tj
4.6998 0 Td
(South)Tj
2.5511 0 Td
(Research)Tj
3.8098 0 Td
(Ethics)Tj
2.6645 0 Td
(Committee)Tj
4.7395 0 Td
(and)Tj
1.7348 0 Td
(was)Tj
1.6951 0 Td
(registered)Tj
4.1556 0 Td
(with)Tj
1.9956 0 Td
(ClinicalTrials.gov)Tj
-28.0458 -1.2983 Td
(\(NCT01541852\).)Tj
6.9391 0 Td
(It)Tj
0.8617 0 Td
(was)Tj
1.6952 0 Td
(conducted)Tj
4.4276 0 Td
(in)Tj
1.0375 0 Td
(accordance)Tj
4.7338 0 Td
(with)Tj
2.0013 0 Td
(the)Tj
1.4683 0 Td
(Declaration)Tj
4.9096 0 Td
(of)Tj
1.0148 0 Td
(Helsinki)Tj
3.5943 0 Td
(and)Tj
1.7348 0 Td
(Good)Tj
-34.418 -1.2982 Td
(Clinical)Tj
3.3165 0 Td
(Practice)Tj
3.4185 0 Td
(standards,)Tj
4.3087 0 Td
(and)Tj
1.7291 0 Td
(written)Tj
3.1124 0 Td
(informed)Tj
3.9742 0 Td
(consent)Tj
3.3278 0 Td
(was)Tj
1.7008 0 Td
(obtained)Tj
3.7304 0 Td
(from)Tj
2.211 0 Td
(all)Tj
1.1452 0 Td
(patients.)Tj
3.5943 0 Td
(The)Tj
-35.5689 -1.3039 Td
(study)Tj
2.3867 0 Td
(was)Tj
1.7008 0 Td
(active)Tj
2.5228 0 Td
(from)Tj
2.2053 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 292.9322 338.9102 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(st)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 300.0188 334.4314 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(April)Tj
2.3073 0 Td
(2012)Tj
2.1203 0 Td
(when)Tj
2.4095 0 Td
(the)Tj
1.4683 0 Td
(first)Tj
1.8028 0 Td
(patient)Tj
3.0104 0 Td
(was)Tj
1.6951 0 Td
(recruited)Tj
3.8551 0 Td
(till)Tj
1.2813 0 Td
(the)Tj
1.4683 0 Td
(6)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 518.9669 338.9102 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(th)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 525.1464 334.4314 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(August)Tj
3.084 0 Td
(2014)Tj
-35.5971 -1.2982 Td
(when)Tj
2.4037 0 Td
(the)Tj
1.4684 0 Td
(final)Tj
2.0012 0 Td
(patient)Tj
3.0104 0 Td
(recruited)Tj
3.8551 0 Td
(completed)Tj
4.405 0 Td
(the)Tj
1.4683 0 Td
(study.)Tj
2.6192 0 Td
(Based)Tj
2.5455 0 Td
(on)Tj
1.2756 0 Td
(sample)Tj
3.0217 0 Td
(size)Tj
1.6838 0 Td
(calculation,)Tj
4.8018 0 Td
(the)Tj
-34.5597 -1.2983 Td
(planned)Tj
3.4639 0 Td
(recruitment)Tj
4.9946 0 Td
(target)Tj
2.5115 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(trial)Tj
1.8369 0 Td
(was)Tj
1.7007 0 Td
(met.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 281.9905 cm
BT
/F12 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Participants)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 264.9826 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Eligible)Tj
3.2087 0 Td
(patients)Tj
3.3676 0 Td
(were)Tj
2.126 0 Td
(aged)Tj
2.0692 0 Td
(5085)Tj
2.6419 0 Td
(years,)Tj
2.4888 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.652 0 Td
(known)Tj
3.0047 0 Td
(diagnosis)Tj
3.9628 0 Td
(of)Tj
1.0148 0 Td
(COPD)Tj
2.9253 0 Td
(\(confirmed)Tj
4.7338 0 Td
(by)Tj
1.1849 0 Td
(post-)Tj
-35.3761 -1.2982 Td
(bronchodilator)Tj
6.2645 0 Td
(spirometry)Tj
4.6091 0 Td
(Forced)Tj
2.999 0 Td
(Expiratory)Tj
4.4787 0 Td
(Lung)Tj
2.2961 0 Td
(Volume)Tj
3.4412 0 Td
(in)Tj
1.0375 0 Td
(1)Tj
0.6916 0 Td
(second/Forced)Tj
6.1228 0 Td
(Vital)Tj
2.16 0 Td
(Capac-)Tj
-34.1005 -1.2983 Td
(ity,)Tj
1.4626 0 Td
(\(FEV)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 235.9559 237.3165 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 239.5275 239.0173 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(/FVC)Tj
2.4377 0 Td
(ratio)Tj
/F13 1 Tf
0 Tc
2.0977 0 Td
(<)Tj
/F7 1 Tf
-0.004 Tc
(0)Tj
/F6 1 Tf
0 Tc
()Tj
/F7 1 Tf
-0.004 Tc
(70\)\),)Tj
3.5943 0 Td
(or)Tj
1.0941 0 Td
(with)Tj
2.0013 0 Td
(spirometry)Tj
4.6091 0 Td
(which)Tj
2.6532 0 Td
(fulfilled)Tj
3.2768 0 Td
(GOLD-Unclassified)Tj
-25.7156 -1.3039 Td
(\(GOLD-U:)Tj
4.609 0 Td
(FEV)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 264.0188 224.3338 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 267.5905 225.9779 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(/FVC)Tj
/F6 1 Tf
0 Tc
2.4321 0 Td
()Tj
/F7 1 Tf
-0.004 Tc
(0)Tj
/F6 1 Tf
0 Tc
()Tj
/F7 1 Tf
-0.004 Tc
(7)Tj
2.2166 0 Td
(and)Tj
1.7292 0 Td
(FEV)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 349.285 224.3338 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 355.011 225.9779 cm
BT
/F13 1 Tf
1 TL
0 0 Td
(<)Tj
/F7 1 Tf
-0.004 Tc
(80%)Tj
2.7042 0 Td
(predicted\))Tj
4.337 0 Td
(categorisation)Tj
5.828 0 Td
([)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(].)Tj
2.0749 0 Td
(However,)Tj
4.0762 0 Td
(no)Tj
-34.52 -1.2982 Td
(GOLD-U)Tj
4.0422 0 Td
(patients)Tj
3.3675 0 Td
(were)Tj
2.1203 0 Td
(recruited)Tj
3.8551 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
1.4682 0 Td
(study.)Tj
2.6192 0 Td
(All)Tj
1.3946 0 Td
(patients)Tj
3.3676 0 Td
(were)Tj
2.1203 0 Td
(current)Tj
3.1861 0 Td
(or)Tj
1.0998 0 Td
(ex-smokers)Tj
4.7962 0 Td
(with)Tj
2.0013 0 Td
(at)Tj
-36.4646 -1.2983 Td
(least)Tj
1.9842 0 Td
(a)Tj
0.652 0 Td
(10-year)Tj
3.2031 0 Td
(pack)Tj
2.092 0 Td
(year)Tj
1.9049 0 Td
(history)Tj
3.0047 0 Td
(and)Tj
1.7291 0 Td
(a)Tj
0.652 0 Td
(plasma)Tj
3.0329 0 Td
(fibrinogen)Tj
/F13 1 Tf
0 Tc
4.4164 0 Td
(>)Tj
/F7 1 Tf
-0.004 Tc
(2)Tj
/F6 1 Tf
0 Tc
()Tj
/F7 1 Tf
-0.004 Tc
(8g/L.)Tj
3.77 0 Td
(This)Tj
1.9843 0 Td
(level)Tj
2.0182 0 Td
(of)Tj
1.0148 0 Td
(plasma)Tj
3.0274 0 Td
(fibrino-)Tj
-34.486 -1.3039 Td
(gen)Tj
1.6554 0 Td
(was)Tj
1.7008 0 Td
(selected)Tj
3.3449 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(stratification)Tj
5.2837 0 Td
(threshold)Tj
4.0138 0 Td
(for)Tj
1.3833 0 Td
(entry)Tj
2.3187 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(study)Tj
2.3924 0 Td
(because)Tj
3.3165 0 Td
(although)Tj
3.7531 0 Td
(there)Tj
2.2677 0 Td
(is)Tj
-36.4079 -1.2983 Td
(no)Tj
1.2756 0 Td
(evidence)Tj
3.7134 0 Td
(of)Tj
1.0147 0 Td
(a)Tj
0.652 0 Td
(fibrinogen)Tj
4.4107 0 Td
(threshold)Tj
4.0138 0 Td
(that)Tj
1.7744 0 Td
(stratifies)Tj
3.5943 0 Td
(for)Tj
1.3833 0 Td
(cardiovascular)Tj
6.0038 0 Td
(risk)Tj
1.7177 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(],)Tj
2.075 0 Td
(values)Tj
2.6645 0 Td
(greater)Tj
-34.2932 -1.2982 Td
(than)Tj
2.0296 0 Td
(2.7g/L)Tj
2.7269 0 Td
(are)Tj
1.4513 0 Td
(associated)Tj
4.252 0 Td
(with)Tj
2.0012 0 Td
(an)Tj
1.2019 0 Td
(increased)Tj
4.0024 0 Td
(risk)Tj
1.7121 0 Td
(of)Tj
1.0148 0 Td
(hospitalisation,)Tj
6.2872 0 Td
(and)Tj
1.7291 0 Td
(worse)Tj
2.5682 0 Td
(FEV)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 527.6976 159.307 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 533.4803 161.0078 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(],)Tj
2.0749 0 Td
(\(and)Tj
-35.4214 -1.2982 Td
(poor)Tj
2.1203 0 Td
(lung)Tj
2.0069 0 Td
(function)Tj
3.6283 0 Td
(defined)Tj
3.2258 0 Td
(by)Tj
1.1849 0 Td
(FEV)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 339.5905 146.3244 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 343.1622 148.0251 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(,)Tj
0.4422 0 Td
(is)Tj
0.8503 0 Td
(similarly)Tj
3.6851 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
1.9955 0 Td
(increased)Tj
4.0025 0 Td
(cardiovascular)Tj
6.0038 0 Td
(risk)Tj
-35.5518 -1.3039 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(]\).)Tj
2.4151 0 Td
(All)Tj
1.3946 0 Td
(patients)Tj
3.3732 0 Td
(maintained)Tj
4.7849 0 Td
(on)Tj
1.2756 0 Td
(their)Tj
2.1088 0 Td
(standard-of-care)Tj
6.8712 0 Td
(medications)Tj
5.0966 0 Td
(prior)Tj
2.2564 0 Td
(to)Tj
1.0205 0 Td
(and)Tj
1.7347 0 Td
(during)Tj
2.9254 0 Td
(the)Tj
-35.257 -1.2982 Td
(study,)Tj
2.6135 0 Td
(including)Tj
4.0422 0 Td
(prescribed)Tj
4.4107 0 Td
(medications)Tj
5.1022 0 Td
(for)Tj
1.3833 0 Td
(cardiovascular)Tj
6.0037 0 Td
(comorbidity)Tj
5.1704 0 Td
(and)Tj
1.7291 0 Td
(COPD.)Tj
3.1521 0 Td
(Full)Tj
-33.6072 -1.2983 Td
(inclusion)Tj
3.9174 0 Td
(and)Tj
1.7292 0 Td
(exclusion)Tj
3.9911 0 Td
(criteria)Tj
3.0728 0 Td
(of)Tj
1.0147 0 Td
(the)Tj
1.4683 0 Td
(trial)Tj
1.8368 0 Td
(including)Tj
4.0422 0 Td
(information)Tj
5.0797 0 Td
(regarding)Tj
4.0932 0 Td
(amendment)Tj
5.0626 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
-36.3341 -1.3039 Td
(trial)Tj
1.8368 0 Td
(inclusion)Tj
3.9175 0 Td
(criteria,)Tj
3.2995 0 Td
(are)Tj
1.4513 0 Td
(reported)Tj
3.6567 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0374 0 Td
(S1)Tj
0 g
1.1678 0 Td
(and)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(S2)Tj
0 g
1.1679 0 Td
(Tables)Tj
2.8063 0 Td
(respectively,)Tj
5.108 0 Td
(and)Tj
1.7291 0 Td
(a)Tj
0.6576 0 Td
(study)Tj
2.3868 0 Td
(flow-chart)Tj
4.3483 0 Td
(of)Tj
-36.3058 -1.2983 Td
(visits)Tj
2.228 0 Td
(and)Tj
1.7291 0 Td
(assessments)Tj
4.972 0 Td
(performed)Tj
4.473 0 Td
(are)Tj
1.4456 0 Td
(shown)Tj
2.8516 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0318 0 Td
(S1)Tj
1.1735 0 Td
(Fig)Tj
0 g
(.)Tj
1.7065 0 Td
(The)Tj
1.7801 0 Td
(trial)Tj
1.8369 0 Td
(consort)Tj
3.2371 0 Td
(diagram)Tj
3.5376 0 Td
(is)Tj
0.8504 0 Td
(shown)Tj
2.846 0 Td
(in)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 377.6881 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(p38)Tj
1.8567 0 Td
(mitogen)Tj
3.7134 0 Td
(activated)Tj
4.1528 0 Td
(protein)Tj
3.2173 0 Td
(kinase)Tj
3.0544 0 Td
(inhibition)Tj
4.0748 0 Td
(and)Tj
1.8567 0 Td
(COPD)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01941)Tj
4.089 0 Td
(97)Tj
0 g
2.0906 0 Td
(March)Tj
2.9622 0 Td
(22,)Tj
1.5874 0 Td
(2018)Tj
34.3562 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
61 0 obj
<>stream
endstream
endobj
62 0 obj
<>stream
endstream
endobj
63 0 obj
<>stream
endstream
endobj
64 0 obj
<>stream
endstream
endobj
65 0 obj
<>stream
endstream
endobj
66 0 obj
<>stream
endstream
endobj
67 0 obj
<>stream
endstream
endobj
68 0 obj
<>stream
endstream
endobj
69 0 obj
<>stream
endstream
endobj
70 0 obj
<>stream
endstream
endobj
71 0 obj
<>stream
endstream
endobj
72 0 obj
<>stream
endstream
endobj
73 0 obj
<>stream
endstream
endobj
74 0 obj
<>stream
endstream
endobj
75 0 obj
<>stream
endstream
endobj
76 0 obj
<>stream
endstream
endobj
77 0 obj
<>stream
endstream
endobj
78 0 obj
<>stream
BT
66.402 0 Td
(17)Tj
ET
Q
endstream
endobj
79 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 82 0 R/Contents 83 0 R/TrimBox[0 0 612 792]>>
endobj
82 0 obj
[84 0 R 85 0 R 86 0 R 87 0 R 88 0 R 89 0 R 90 0 R 91 0 R]
endobj
84 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.g001)>>
endobj
85 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.s007)>>
endobj
86 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.s002)>>
endobj
87 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.s004)>>
endobj
88 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.g002)>>
endobj
89 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref019)>>
endobj
90 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194197.ref020)>>
endobj
91 0 obj
<>/Border[0 0 0]/A 92 0 R>>
endobj
92 0 obj
<>
endobj
83 0 obj
[93 0 R 94 0 R 95 0 R 96 0 R 97 0 R 98 0 R 99 0 R 100 0 R 101 0 R 102 0 R]
endobj
93 0 obj
<>stream
q
0.83 0.64 0.02 0 k
200.0126 706.337 m
219.5717 706.337 l
h
f*
388.9701 706.337 m
422.9291 706.337 l
h
f*
302.6835 693.2976 m
353.8772 693.2976 l
h
f*
200.0126 502.4126 m
247.0677 502.4126 l
h
f*
535.6346 437.3858 m
555.1937 437.3858 l
h
f*
439.8803 294.4063 m
449.4047 294.4063 l
h
f*
448.1575 229.3795 m
457.6819 229.3795 l
h
f*
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Fig)Tj
1.4796 0 Td
(1)Tj
0 g
0.6973 0 Td
(with)Tj
1.9956 0 Td
(further)Tj
3.0274 0 Td
(information)Tj
5.074 0 Td
(also)Tj
1.7688 0 Td
(provided)Tj
3.8154 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0375 0 Td
(S3)Tj
1.1735 0 Td
(Table)Tj
0 g
(.)Tj
2.6646 0 Td
(The)Tj
1.7858 0 Td
(consort)Tj
3.2315 0 Td
(checklist)Tj
3.6906 0 Td
(for)Tj
1.3833 0 Td
(the)Tj
1.474 0 Td
(EVO-)Tj
-34.2989 -1.3039 Td
(LUTION)Tj
3.9287 0 Td
(trial)Tj
1.8369 0 Td
(is)Tj
0.8447 0 Td
(found)Tj
2.6192 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0375 0 Td
(S1)Tj
1.1735 0 Td
(Appendix)Tj
0 g
(.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 667.9559 cm
BT
/F12 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Randomisation)Tj
6.6378 0 Td
(and)Tj
1.7906 0 Td
(masking)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 650.948 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Subjects)Tj
3.4922 0 Td
(were)Tj
2.1203 0 Td
(randomised)Tj
5.0116 0 Td
(\(1:1\))Tj
2.075 0 Td
(to)Tj
1.0261 0 Td
(receive)Tj
3.0047 0 Td
(either)Tj
2.5342 0 Td
(losmapimod)Tj
5.227 0 Td
(7.5mg)Tj
2.6816 0 Td
(or)Tj
1.0942 0 Td
(matching)Tj
4.0081 0 Td
(placebo)Tj
-32.275 -1.3039 Td
(twice)Tj
2.313 0 Td
(daily)Tj
2.1543 0 Td
(for)Tj
1.3833 0 Td
(16)Tj
1.1736 0 Td
(weeks.)Tj
2.8346 0 Td
(An)Tj
1.4513 0 Td
(online)Tj
2.7609 0 Td
(coded)Tj
2.6306 0 Td
(program)Tj
3.702 0 Td
(was)Tj
1.7008 0 Td
(used)Tj
2.0579 0 Td
(to)Tj
1.0262 0 Td
(randomise)Tj
4.4787 0 Td
(patients)Tj
3.3675 0 Td
(stratified)Tj
-33.0347 -1.2982 Td
(by)Tj
1.1792 0 Td
(trial)Tj
1.8368 0 Td
(site.)Tj
1.7971 0 Td
(All)Tj
1.3947 0 Td
(trial)Tj
1.8368 0 Td
(personnel,)Tj
4.3937 0 Td
(including)Tj
4.0422 0 Td
(investigators)Tj
5.2781 0 Td
(giving)Tj
2.6872 0 Td
(trial)Tj
1.8368 0 Td
(interventions,)Tj
5.76 0 Td
(assessing)Tj
3.8041 0 Td
(out-)Tj
-35.8467 -1.2983 Td
(comes,)Tj
2.9763 0 Td
(and)Tj
1.7348 0 Td
(analysis)Tj
3.3222 0 Td
(of)Tj
1.0148 0 Td
(data,)Tj
2.143 0 Td
(and)Tj
1.7291 0 Td
(patients)Tj
3.3675 0 Td
(were)Tj
2.1203 0 Td
(blinded)Tj
3.2712 0 Td
(throughout)Tj
4.7792 0 Td
(the)Tj
1.4683 0 Td
(study)Tj
2.3868 0 Td
(to)Tj
1.0261 0 Td
(treatment)Tj
4.1386 0 Td
(allo-)Tj
-35.4782 -1.2983 Td
(cation.)Tj
2.9196 0 Td
(Study)Tj
2.5058 0 Td
(medication)Tj
4.7395 0 Td
(was)Tj
1.6951 0 Td
(provided)Tj
3.8211 0 Td
(by)Tj
1.1792 0 Td
(GSK.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 572.485 cm
BT
/F12 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Assessments)Tj
5.4378 0 Td
(for)Tj
1.4693 0 Td
(primary)Tj
3.6331 0 Td
(endpoint)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 211.9748 555.4771 cm
BT
/F12 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Vascular)Tj
3.8891 0 Td
(PET/CT)Tj
3.6793 0 Td
(imaging.)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 332.2771 559.8992 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(18)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 339.3637 555.4771 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(F-Fluorodeoxyglucose)Tj
9.1218 0 Td
(PET)Tj
1.9559 0 Td
(paired)Tj
2.7609 0 Td
(with)Tj
1.9956 0 Td
(attenuated)Tj
4.439 0 Td
(cor-)Tj
-34.2082 -1.3039 Td
(rected)Tj
2.6872 0 Td
(computed)Tj
4.2633 0 Td
(tomography)Tj
5.125 0 Td
(\(FDG)Tj
2.5398 0 Td
(PET/CT\))Tj
3.9004 0 Td
(imaging)Tj
3.4866 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(aorta)Tj
2.2677 0 Td
(and)Tj
1.7292 0 Td
(carotid)Tj
3.05 0 Td
(arteries)Tj
3.1691 0 Td
(was)Tj
-34.7014 -1.2982 Td
(performed)Tj
4.4674 0 Td
(before,)Tj
2.965 0 Td
(and)Tj
1.7291 0 Td
(at)Tj
0.9525 0 Td
(16)Tj
1.1735 0 Td
(weeks)Tj
2.6079 0 Td
(of)Tj
1.0147 0 Td
(treatment,)Tj
4.3596 0 Td
(to)Tj
1.0262 0 Td
(evaluate)Tj
3.4639 0 Td
(tracer)Tj
2.5398 0 Td
(uptake)Tj
2.9197 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(surrogate)Tj
3.9798 0 Td
(mea-)Tj
-34.8658 -1.2983 Td
(sure)Tj
1.9049 0 Td
(of)Tj
1.0148 0 Td
(arterial)Tj
3.0614 0 Td
(inflammation.)Tj
5.9244 0 Td
(Further)Tj
3.271 0 Td
(detailed)Tj
3.3676 0 Td
(information)Tj
5.0739 0 Td
(regarding)Tj
4.0932 0 Td
(imaging)Tj
3.4866 0 Td
(is)Tj
0.8504 0 Td
(explained)Tj
4.0705 0 Td
(in)Tj
0.83 0.64 0.02 0 k
-36.1187 -1.2983 Td
(S1)Tj
1.1679 0 Td
(Methods)Tj
0 g
(.)Tj
3.9855 0 Td
(For)Tj
1.627 0 Td
(image)Tj
2.6306 0 Td
(analysis,)Tj
3.5489 0 Td
(Osirix)Tj
2.6985 0 Td
(open-source)Tj
5.1817 0 Td
(DICOM)Tj
3.6 0 Td
(software)Tj
3.583 0 Td
(v5)Tj
/F6 1 Tf
0 Tc
()Tj
/F7 1 Tf
-0.004 Tc
(6)Tj
1.8992 0 Td
(\(Geneva,)Tj
3.787 0 Td
(Switzer-)Tj
-33.7093 -1.3039 Td
(land\))Tj
2.3131 0 Td
(was)Tj
1.7008 0 Td
(used.)Tj
2.2847 0 Td
(A)Tj
0.907 0 Td
(region)Tj
2.8007 0 Td
(of)Tj
1.0148 0 Td
(interest)Tj
3.2143 0 Td
(\(ROI\))Tj
2.6079 0 Td
(including)Tj
4.0422 0 Td
(arterial)Tj
3.0614 0 Td
(wall)Tj
1.8311 0 Td
(and)Tj
1.7291 0 Td
(lumen)Tj
2.7893 0 Td
(was)Tj
1.7008 0 Td
(drawn)Tj
2.7836 0 Td
(on)Tj
-34.7808 -1.2982 Td
(each)Tj
2.0296 0 Td
(axial)Tj
2.0636 0 Td
(slice)Tj
1.9446 0 Td
(of)Tj
1.0148 0 Td
(artery)Tj
2.5681 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.474 0 Td
(co-registered)Tj
5.4311 0 Td
(PET/CT)Tj
3.5659 0 Td
(scan)Tj
1.9843 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.474 0 Td
(maximum)Tj
4.371 0 Td
(Standardised)Tj
-30.9257 -1.2983 Td
(Uptake)Tj
3.1238 0 Td
(Value)Tj
2.5455 0 Td
(\(SUVmax\))Tj
4.524 0 Td
(recorded.)Tj
4.0251 0 Td
(Subsequently,)Tj
5.743 0 Td
(each)Tj
2.0296 0 Td
(ROI)Tj
1.9275 0 Td
(was)Tj
1.7008 0 Td
(normalised)Tj
4.7281 0 Td
(by)Tj
1.1793 0 Td
(blood)Tj
2.5171 0 Td
(FDG)Tj
-34.0438 -1.3039 Td
(concentration)Tj
5.8167 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(superior)Tj
3.5659 0 Td
(vena)Tj
2.0806 0 Td
(cava)Tj
1.9672 0 Td
(or)Tj
1.0998 0 Td
(jugular)Tj
3.0501 0 Td
(vein)Tj
1.9105 0 Td
(\(for)Tj
1.7292 0 Td
(carotids\),)Tj
3.9741 0 Td
(to)Tj
1.0261 0 Td
(yield)Tj
2.1373 0 Td
(an)Tj
1.2019 0 Td
(arterial)Tj
3.0671 0 Td
(maxi-)Tj
-35.1323 -1.2983 Td
(mum)Tj
2.3868 0 Td
(tissue-to-blood)Tj
6.2588 0 Td
(ratio)Tj
2.0977 0 Td
(\(TBR\))Tj
2.7099 0 Td
(as)Tj
1.0147 0 Td
(a)Tj
0.6576 0 Td
(quantitative)Tj
4.9776 0 Td
(measure)Tj
3.583 0 Td
(of)Tj
1.0148 0 Td
(arterial)Tj
3.0614 0 Td
(tracer)Tj
2.5455 0 Td
(uptake)Tj
2.914 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(2)Tj
0 g
(\).)Tj
-35.0416 -1.2983 Td
(Slices)Tj
2.4151 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6576 0 Td
(TBR)Tj
/F13 1 Tf
0 Tc
2.0296 0 Td
(>)Tj
/F7 1 Tf
-0.004 Tc
(1)Tj
/F6 1 Tf
0 Tc
()Tj
/F7 1 Tf
-0.004 Tc
(6,)Tj
2.4435 0 Td
(deemed)Tj
3.3618 0 Td
(`active)Tj
2.7495 0 Td
(slices')Tj
2.5172 0 Td
(were)Tj
2.1203 0 Td
(included)Tj
3.7133 0 Td
(in)Tj
1.0375 0 Td
(analyses.)Tj
-23.8448 -1.3039 Td
(The)Tj
1.7858 0 Td
(arteries)Tj
3.1692 0 Td
(were)Tj
2.1203 0 Td
(analysed)Tj
3.651 0 Td
(as)Tj
1.0148 0 Td
(six)Tj
1.3151 0 Td
(arterial)Tj
3.0671 0 Td
(territories:)Tj
4.405 0 Td
(the)Tj
1.4683 0 Td
(ascending,)Tj
4.4447 0 Td
(descending,)Tj
4.9606 0 Td
(abdominal)Tj
-32.5981 -1.2982 Td
(aorta)Tj
2.2621 0 Td
(and)Tj
1.7291 0 Td
(right)Tj
2.1543 0 Td
(and)Tj
1.7291 0 Td
(left)Tj
1.474 0 Td
(carotid)Tj
3.0501 0 Td
(arteries,)Tj
3.3958 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4683 0 Td
(aortic)Tj
2.5228 0 Td
(arch.)Tj
2.1997 0 Td
(For)Tj
1.6271 0 Td
(each)Tj
2.0296 0 Td
(arterial)Tj
3.0671 0 Td
(territory)Tj
3.5829 0 Td
(and)Tj
1.7291 0 Td
(each)Tj
-35.7502 -1.2983 Td
(scan,)Tj
2.211 0 Td
(the)Tj
1.4684 0 Td
(average)Tj
3.2258 0 Td
(TBR)Tj
2.0352 0 Td
(was)Tj
1.7008 0 Td
(calculated)Tj
4.2008 0 Td
(by)Tj
1.1849 0 Td
(taking)Tj
2.7269 0 Td
(the)Tj
1.4684 0 Td
(mean)Tj
2.4491 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(TBR)Tj
2.0296 0 Td
(across)Tj
2.6816 0 Td
(all)Tj
1.1451 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(slices)Tj
2.3017 0 Td
(in)Tj
-35.7956 -1.2983 Td
(the)Tj
1.4684 0 Td
(territory)Tj
3.5829 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6576 0 Td
(TBR)Tj
/F13 1 Tf
0 Tc
2.0296 0 Td
(>)Tj
/F7 1 Tf
-0.004 Tc
(1.6.)Tj
2.3925 0 Td
(This)Tj
1.9898 0 Td
(produced)Tj
4.0478 0 Td
(the)Tj
1.4684 0 Td
(TBR)Tj
2.0295 0 Td
(of)Tj
1.0148 0 Td
(each)Tj
2.0296 0 Td
(arterial)Tj
3.0671 0 Td
(territory,)Tj
3.8097 0 Td
(for)Tj
1.3833 0 Td
(each)Tj
2.0296 0 Td
(scan.)Tj
-34.9962 -1.3039 Td
(Change)Tj
3.2825 0 Td
(in)Tj
1.0318 0 Td
(TBR)Tj
2.0353 0 Td
(was)Tj
1.7008 0 Td
(pre-defined)Tj
4.8869 0 Td
(as)Tj
1.0147 0 Td
(the)Tj
1.4683 0 Td
(change)Tj
3.0444 0 Td
(in)Tj
1.0375 0 Td
(average)Tj
3.2258 0 Td
(TBR,)Tj
2.2563 0 Td
(from)Tj
2.2054 0 Td
(post-)Tj
2.2563 0 Td
(to)Tj
1.0205 0 Td
(pre-dose)Tj
3.702 0 Td
(scans.)Tj
-32.9723 -1.2982 Td
(The)Tj
1.7745 0 Td
(index)Tj
2.8346 0 Td
(vessel)Tj
2.8744 0 Td
(\(defined)Tj
3.5546 0 Td
(as)Tj
1.0091 0 Td
(the)Tj
1.4569 0 Td
(arterial)Tj
3.0557 0 Td
(territory)Tj
3.5773 0 Td
(with)Tj
1.9843 0 Td
(the)Tj
1.4626 0 Td
(highest)Tj
3.0784 0 Td
(average)Tj
3.2202 0 Td
(TBR)Tj
2.0239 0 Td
(at)Tj
0.9411 0 Td
(baseline\))Tj
-34.0438 -1.2983 Td
(was)Tj
1.6951 0 Td
(selected)Tj
3.3506 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
/F14 1 Tf
1.4683 0 Td
[()]TJ
0.7086 0 Td
[()11()-9()4()11()-9()]TJ
/F7 1 Tf
2.4152 0 Td
(focus)Tj
2.3243 0 Td
(of)Tj
1.0147 0 Td
(interest)Tj
3.2145 0 Td
(to)Tj
1.0261 0 Td
(determine)Tj
4.32 0 Td
(change)Tj
3.0444 0 Td
(over)Tj
1.9786 0 Td
(time)Tj
2.0296 0 Td
(with)Tj
1.9956 0 Td
(treatment)Tj
4.1328 0 Td
(or)Tj
-35.7332 -1.3039 Td
(placebo.)Tj
3.5036 0 Td
(Arterial)Tj
3.3165 0 Td
(territories)Tj
4.1783 0 Td
(that)Tj
1.7801 0 Td
(could)Tj
2.449 0 Td
(be)Tj
1.1509 0 Td
(the)Tj
1.4683 0 Td
(index)Tj
2.4548 0 Td
(vessel)Tj
2.4888 0 Td
(included)Tj
3.7134 0 Td
(the)Tj
1.4683 0 Td
(ascending,)Tj
4.4447 0 Td
(descending,)Tj
-32.4167 -1.2983 Td
(abdominal)Tj
4.5071 0 Td
(aorta)Tj
2.2677 0 Td
(or)Tj
1.0998 0 Td
(either)Tj
2.5285 0 Td
(carotid)Tj
3.0501 0 Td
(artery,)Tj
2.8005 0 Td
(but)Tj
1.5534 0 Td
(not)Tj
1.5703 0 Td
(the)Tj
1.4684 0 Td
(aortic)Tj
2.5228 0 Td
(arch)Tj
1.9786 0 Td
(because)Tj
3.3165 0 Td
(higher)Tj
2.8063 0 Td
(inter-observer)Tj
-31.47 -1.2983 Td
(variability)Tj
4.2179 0 Td
(in)Tj
1.0375 0 Td
(analysing)Tj
3.9798 0 Td
(this)Tj
1.6725 0 Td
(region)Tj
2.8062 0 Td
(was)Tj
1.6951 0 Td
(previously)Tj
4.3539 0 Td
(reported.)Tj
3.8835 0 Td
([)Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(])Tj
1.8538 0 Td
(Additionally,)Tj
5.4539 0 Td
(we)Tj
1.3266 0 Td
(report)Tj
2.7099 0 Td
(the)Tj
-34.9906 -1.3039 Td
(change)Tj
3.0387 0 Td
(in)Tj
1.0375 0 Td
(TBR)Tj
2.0353 0 Td
(in)Tj
1.0318 0 Td
(each)Tj
2.0296 0 Td
(arterial)Tj
3.067 0 Td
(region)Tj
2.8006 0 Td
(individually,)Tj
5.2157 0 Td
(including)Tj
4.0421 0 Td
(the)Tj
1.4684 0 Td
(aortic)Tj
2.5228 0 Td
(arch.)Tj
2.1997 0 Td
(All)Tj
1.4003 0 Td
(scans)Tj
2.3471 0 Td
(were)Tj
-34.2366 -1.2982 Td
(analysed)Tj
3.651 0 Td
(by)Tj
1.1792 0 Td
(an)Tj
1.2019 0 Td
(experienced)Tj
5.0343 0 Td
(reader,)Tj
2.9989 0 Td
(anonymised)Tj
5.108 0 Td
(to)Tj
1.0262 0 Td
(patient)Tj
3.0104 0 Td
(identifiable)Tj
4.7168 0 Td
(information,)Tj
5.3007 0 Td
(treatment)Tj
-33.2274 -1.2983 Td
(group,)Tj
2.8346 0 Td
(and)Tj
1.7292 0 Td
(visit)Tj
1.8652 0 Td
(number.)Tj
/F12 1 Tf
-5.2328 -1.3039 Td
(Endothelial)Tj
5.057 0 Td
(function.)Tj
/F7 1 Tf
4.6148 0 Td
(Endothelial)Tj
4.8131 0 Td
(function)Tj
3.6283 0 Td
(was)Tj
1.7008 0 Td
(assessed)Tj
3.4696 0 Td
(by)Tj
1.1848 0 Td
(brachial)Tj
3.4299 0 Td
(artery)Tj
2.5739 0 Td
(FMD)Tj
2.3754 0 Td
(pre-)Tj
1.8822 0 Td
(and)Tj
-35.926 -1.2983 Td
(post-treatment)Tj
6.1682 0 Td
(using)Tj
2.3924 0 Td
(established)Tj
4.5921 0 Td
(ultrasonography)Tj
6.7917 0 Td
(techniques)Tj
4.5297 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
2.0749 0 Td
(FMD)Tj
2.3811 0 Td
(was)Tj
1.6951 0 Td
(defined)Tj
3.2258 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
-34.8658 -1.2983 Td
(maximum)Tj
4.371 0 Td
(percentage)Tj
4.5468 0 Td
(increase)Tj
3.4752 0 Td
(in)Tj
1.0375 0 Td
(artery)Tj
2.5737 0 Td
(diameter,)Tj
4.0082 0 Td
(after)Tj
2.0353 0 Td
(release)Tj
2.9026 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(blood)Tj
2.5171 0 Td
(pressure)Tj
3.5773 0 Td
(cuff)Tj
1.7462 0 Td
(inflated)Tj
-34.4577 -1.2982 Td
(to)Tj
1.0262 0 Td
(supra-systolic)Tj
5.6976 0 Td
(pressure)Tj
3.5773 0 Td
(for)Tj
1.3889 0 Td
(5)Tj
0.6917 0 Td
(minutes)Tj
3.4695 0 Td
(to)Tj
1.0204 0 Td
(induce)Tj
2.9424 0 Td
(ischemia)Tj
3.7417 0 Td
(distal)Tj
2.3527 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
1.4683 0 Td
(site)Tj
1.5704 0 Td
(of)Tj
1.0148 0 Td
(measurement)Tj
-30.9881 -1.3039 Td
(\(reactive)Tj
3.6567 0 Td
(hyperemia\).)Tj
5.023 0 Td
(After)Tj
2.2847 0 Td
(a)Tj
0.6519 0 Td
(10-minute)Tj
4.4106 0 Td
(break,)Tj
2.6759 0 Td
(endothelial-independent)Tj
10.0743 0 Td
(dilatation)Tj
4.0478 0 Td
(was)Tj
1.7008 0 Td
(then)Tj
-34.5257 -1.2983 Td
(assessed.)Tj
3.6964 0 Td
(This)Tj
1.9899 0 Td
(is)Tj
0.8447 0 Td
(the)Tj
1.4683 0 Td
(maximum)Tj
4.3767 0 Td
(percentage)Tj
4.5466 0 Td
(increase)Tj
3.4753 0 Td
(in)Tj
1.0318 0 Td
(artery)Tj
2.5738 0 Td
(diameter)Tj
3.7871 0 Td
(after)Tj
2.0353 0 Td
(administration)Tj
6.1681 0 Td
(of)Tj
-35.994 -1.2983 Td
(25)Tj
/F15 1 Tf
1.1679 0 Td
[()]TJ
/F7 1 Tf
(g)Tj
1.1962 0 Td
(of)Tj
1.0148 0 Td
(sublingual)Tj
4.3483 0 Td
(glyceryl)Tj
3.3052 0 Td
(trinitrate)Tj
3.7983 0 Td
(\(GTN\).)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 139.011 cm
BT
/F12 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Assessments)Tj
5.4378 0 Td
(for)Tj
1.4693 0 Td
(secondary)Tj
4.4173 0 Td
(endpoints)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 211.9748 122.0031 cm
BT
/F12 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Arterial)Tj
3.5376 0 Td
(stiffness.)Tj
/F7 1 Tf
4.473 0 Td
(Assessments)Tj
5.2214 0 Td
(were)Tj
2.1203 0 Td
(performed)Tj
4.473 0 Td
(pre-)Tj
1.8822 0 Td
(and)Tj
1.7292 0 Td
(post-treatment.)Tj
6.3949 0 Td
(After)Tj
2.2847 0 Td
(a)Tj
0.6519 0 Td
(15-min-)Tj
-33.9644 -1.2982 Td
(ute)Tj
1.4683 0 Td
(rest,)Tj
1.8992 0 Td
(seated)Tj
2.6872 0 Td
(brachial)Tj
3.4299 0 Td
(blood)Tj
2.5172 0 Td
(pressure)Tj
3.5773 0 Td
(was)Tj
1.6951 0 Td
(recorded)Tj
3.7984 0 Td
(\(OMRON-750CP,)Tj
7.5287 0 Td
(Omron)Tj
3.2145 0 Td
(Corp,)Tj
2.5058 0 Td
(Japan\).)Tj
-34.3216 -1.3039 Td
(Radial)Tj
2.7495 0 Td
(artery)Tj
2.5739 0 Td
(waveforms)Tj
4.5637 0 Td
(were)Tj
2.1203 0 Td
(then)Tj
2.0183 0 Td
(obtained)Tj
3.736 0 Td
(using)Tj
2.3868 0 Td
(a)Tj
0.6519 0 Td
(high-fidelity)Tj
5.1307 0 Td
(micromanometer)Tj
7.2567 0 Td
(\(SPC-301,)Tj
-33.1878 -1.2983 Td
(Millar)Tj
2.6758 0 Td
(Instruments,)Tj
5.3461 0 Td
(Texas,)Tj
2.7383 0 Td
(USA\))Tj
2.4548 0 Td
(and)Tj
1.7291 0 Td
(recorded)Tj
3.7984 0 Td
(using)Tj
2.3868 0 Td
(Sphygmocor)Tj
5.2894 0 Td
(software)Tj
3.5886 0 Td
(\(AtCor)Tj
3.0841 0 Td
(Medical,)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 377.6881 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(p38)Tj
1.8567 0 Td
(mitogen)Tj
3.7134 0 Td
(activated)Tj
4.1528 0 Td
(protein)Tj
3.2173 0 Td
(kinase)Tj
3.0544 0 Td
(inhibition)Tj
4.0748 0 Td
(and)Tj
1.8567 0 Td
(COPD)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01941)Tj
4.089 0 Td
(97)Tj
0 g
2.0906 0 Td
(March)Tj
2.9622 0 Td
(22,)Tj
1.5874 0 Td
(2018)Tj
34.3562 0 Td
(4)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
94 0 obj
<>stream
endstream
endobj
95 0 obj
<>stream
endstream
endobj
96 0 obj
<>stream
endstream
endobj
97 0 obj
<>stream
endstream
endobj
98 0 obj
<>stream
endstream
endobj
99 0 obj
<>stream
endstream
endobj
100 0 obj
<>stream
endstream
endobj
101 0 obj
<>stream
endstream
endobj
102 0 obj
<>stream
BT
66.402 0 Td
(17)Tj
ET
Q
endstream
endobj
103 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 105 0 R/Contents 106 0 R/TrimBox[0 0 612 792]>>
endobj
104 0 obj
<>stream
xEڇ̢gs:s>=ϜLN(` A(*FA%'$ 63ӳꪷ[@ƚQD@D@D@D@D@D@D@D@D@D@D@D@D@D@D@D@D@D@D@D@@Qչs7Oؒuu
[ob,n=Ox#S&]ϜڪT@vUу})V;dڭa<-Q']4n=Y+" " " " " " " "A)rruOh%7]0yf.CHh#U-" " " " " " " "]F)~&]svOh)IE떓" " " " " " " " ! ]4{n 0;C[N -5If9Iְ`Mgi4!dJ7h}d晈vU]?\60dB@t@R2y
6[nsΝ6m(tܜR
tY+O6zkƍpXfٳ#kƌ
7ojg<:L@(MLl˖-[]s̙