%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
David Hervás, Victoria Fornés-Ferrer, Ana Pilar Gómez-Escribano, María Dolores Sequedo, Carmen Peiró, José María Millán, Rafael P. Vázquez-Manrique
Metformin intake associates with better cognitive function in patients with Huntington's disease
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 13 0 R/Contents 14 0 R/TrimBox[0 0 612 792]>>
endobj
13 0 obj
[15 0 R 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 27 0 R 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]
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref008)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref009)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref008)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref008)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref010)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref011)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref012)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref013)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref008)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref008)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref009)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref014)>>
endobj
27 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref015)>>
endobj
28 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref016)>>
endobj
29 0 obj
<>/Border[0 0 0]/A 37 0 R>>
endobj
37 0 obj
<>
endobj
30 0 obj
<>/Border[0 0 0]/A 38 0 R>>
endobj
38 0 obj
<>
endobj
31 0 obj
<>/Border[0 0 0]/A 39 0 R>>
endobj
39 0 obj
<>
endobj
32 0 obj
<>/Border[0 0 0]/A 40 0 R>>
endobj
40 0 obj
<>
endobj
33 0 obj
<>/Border[0 0 0]/A 41 0 R>>
endobj
41 0 obj
<>
endobj
34 0 obj
<>/Border[0 0 0]/A 42 0 R>>
endobj
42 0 obj
<>
endobj
35 0 obj
<>/Border[0 0 0]/A 43 0 R>>
endobj
43 0 obj
<>
endobj
36 0 obj
<>/Border[0 0 0]/A 44 0 R>>
endobj
44 0 obj
<>
endobj
14 0 obj
[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]
endobj
45 0 obj
<>stream
q
0.83 0.64 0.02 0 k
500.9386 693.2976 m
505.7575 693.2976 l
h
f*
508.0819 693.2976 m
512.9575 693.2976 l
h
f*
243.6094 680.315 m
248.4283 680.315 l
h
f*
331.9937 654.3496 m
336.8693 654.3496 l
h
f*
357.6189 641.3102 m
367.2567 641.3102 l
h
f*
546.1228 641.3102 m
555.8173 641.3102 l
h
f*
512.7307 615.3449 m
522.4252 615.3449 l
h
f*
524.7496 615.3449 m
534.3874 615.3449 l
h
f*
374.0598 576.3402 m
378.8787 576.3402 l
h
f*
400.1953 563.3008 m
405.0142 563.3008 l
h
f*
548.1638 550.3181 m
552.9827 550.3181 l
h
f*
410.2299 524.2961 m
419.8677 524.2961 l
h
f*
422.1921 524.2961 m
431.8866 524.2961 l
h
f*
535.0677 459.326 m
544.5921 459.326 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 211.9748 707.4141 cm
BT
/F6 1 Tf
1 TL
0.003 Tc
0 0 Td
(Adenosine)Tj
4.575 0 Td
(monophosphate-activ)Tj
8.8611 0 Td
(ated)Tj
1.9275 0 Td
(protein)Tj
3.2032 0 Td
(kinase)Tj
2.7949 0 Td
(\(AMPK\))Tj
3.7474 0 Td
(has)Tj
1.5647 0 Td
(shown)Tj
2.8856 0 Td
(potential)Tj
3.8211 0 Td
(as)Tj
1.0318 0 Td
(an)Tj
-35.6085 -1.3039 Td
(HD)Tj
1.7347 0 Td
(druggable)Tj
4.252 0 Td
(target)Tj
2.5511 0 Td
(as)Tj
1.0318 0 Td
(its)Tj
1.1679 0 Td
(activation)Tj
4.2236 0 Td
(induces)Tj
3.3449 0 Td
(improved)Tj
4.1669 0 Td
(neuronal)Tj
3.8834 0 Td
(survival)Tj
3.3902 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(])Tj
2.1147 0 Td
(and)Tj
1.7461 0 Td
(mHtt)Tj
-33.6073 -1.2982 Td
(clearance)Tj
4.0081 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(])Tj
1.4003 0 Td
(in)Tj
/F7 1 Tf
1.0488 0 Td
[()12()]TJ
1.0262 0 Td
[()-13()14()7()20()]TJ
/F6 1 Tf
2.0806 0 Td
(and)Tj
/F7 1 Tf
1.7518 0 Td
[()12()]TJ
1.0318 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8482 0 Td
(models)Tj
3.1464 0 Td
(of)Tj
1.0261 0 Td
(HD.)Tj
1.9729 0 Td
(In)Tj
1.1225 0 Td
(some)Tj
2.3584 0 Td
(cases)Tj
2.2564 0 Td
(a)Tj
0.6633 0 Td
(neuroprotective)Tj
6.6841 0 Td
(effect)Tj
2.4094 0 Td
(has)Tj
-35.8353 -1.2983 Td
(been)Tj
2.1486 0 Td
(observed)Tj
3.8494 0 Td
(when)Tj
2.4321 0 Td
(AMPK)Tj
3.0614 0 Td
(activation)Tj
4.2236 0 Td
(is)Tj
0.8617 0 Td
(induced)Tj
3.515 0 Td
(prior)Tj
2.2847 0 Td
(to)Tj
1.0431 0 Td
(the)Tj
1.491 0 Td
(occurrence)Tj
4.7339 0 Td
(of)Tj
1.0261 0 Td
(substantial)Tj
4.5808 0 Td
(func-)Tj
-35.2514 -1.2983 Td
(tional)Tj
2.5624 0 Td
(alterations)Tj
4.4844 0 Td
(and)Tj
1.7518 0 Td
(cell)Tj
1.5874 0 Td
(death)Tj
2.4661 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
1.6328 0 Td
(This)Tj
2.0126 0 Td
(is)Tj
0.8617 0 Td
(the)Tj
1.491 0 Td
(case)Tj
1.8879 0 Td
(of)Tj
1.0318 0 Td
(models)Tj
3.1464 0 Td
(of)Tj
1.0262 0 Td
(early-stage)Tj
4.5637 0 Td
(HD)Tj
1.7348 0 Td
(such)Tj
2.0863 0 Td
(as)Tj
/F7 1 Tf
1.0318 0 Td
[()-2( )6(\n)]TJ
-35.3591 -1.3039 Td
[()6()11()8()6( )22()4(\r)12()14()7()-4()]TJ
4.7791 0 Td
[(\n)15()4(\n)9()2( )16()]TJ
/F6 1 Tf
3.0444 0 Td
(expressing)Tj
4.4901 0 Td
(polyQs)Tj
3.0954 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(])Tj
1.8822 0 Td
(and)Tj
1.7518 0 Td
(striatal)Tj
2.9877 0 Td
(neurons)Tj
3.5546 0 Td
(from)Tj
2.2337 0 Td
(Hdh111Q)Tj
4.2633 0 Td
(mice)Tj
2.1826 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(].)Tj
-34.2649 -1.2982 Td
(Metformin)Tj
4.6997 0 Td
(is)Tj
0.8618 0 Td
(an)Tj
1.2132 0 Td
(antiglycemic)Tj
5.3745 0 Td
(drug)Tj
2.1429 0 Td
(commonly)Tj
4.6035 0 Td
(used)Tj
2.0863 0 Td
(for)Tj
1.4059 0 Td
(the)Tj
1.491 0 Td
(treatment)Tj
4.201 0 Td
(of)Tj
1.0261 0 Td
(type-2)Tj
2.7836 0 Td
(diabetes)Tj
3.5206 0 Td
(that)Tj
-35.4101 -1.2983 Td
(has)Tj
1.5647 0 Td
(a)Tj
0.6576 0 Td
(well)Tj
1.8482 0 Td
(described)Tj
4.1158 0 Td
(AMPK)Tj
3.0558 0 Td
(activator)Tj
3.7757 0 Td
(effect,)Tj
2.6362 0 Td
(although)Tj
3.8097 0 Td
(it)Tj
0.7994 0 Td
(also)Tj
1.7972 0 Td
(has)Tj
1.5647 0 Td
(other)Tj
2.3811 0 Td
(targets)Tj
2.9196 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(].)Tj
3.3109 0 Td
(Experi-)Tj
-34.2366 -1.3039 Td
(ments)Tj
2.7042 0 Td
(in)Tj
1.0488 0 Td
(several)Tj
2.982 0 Td
(systems)Tj
3.3505 0 Td
(suggest)Tj
3.1692 0 Td
(that)Tj
1.8084 0 Td
(metformin)Tj
4.6262 0 Td
(might)Tj
2.6305 0 Td
(have)Tj
2.092 0 Td
(a)Tj
0.6576 0 Td
(beneficial)Tj
4.1215 0 Td
(effect)Tj
2.4038 0 Td
(on)Tj
1.2926 0 Td
(HD)Tj
1.7348 0 Td
(mod-)Tj
-34.6221 -1.2983 Td
(els.)Tj
1.5023 0 Td
(In)Tj
1.1225 0 Td
(a)Tj
/F7 1 Tf
0.6633 0 Td
[()]TJ
/F6 1 Tf
(.)Tj
/F7 1 Tf
1.0772 0 Td
[(\n)15()4(\n)9()2( )16()]TJ
/F6 1 Tf
3.05 0 Td
(model)Tj
2.778 0 Td
(in)Tj
1.0488 0 Td
(which)Tj
2.6872 0 Td
(worms)Tj
2.9934 0 Td
(express)Tj
3.1918 0 Td
(toxic)Tj
2.2166 0 Td
(polyQs)Tj
3.0954 0 Td
(in)Tj
1.0489 0 Td
(neurons,)Tj
3.7927 0 Td
(the)Tj
1.491 0 Td
(presence)Tj
3.7644 0 Td
(of)Tj
-35.5235 -1.2983 Td
(metformin)Tj
4.626 0 Td
(reduced)Tj
3.4923 0 Td
(neuronal)Tj
3.8835 0 Td
(impairment)Tj
5.0569 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
1.6271 0 Td
(Furthermore,)Tj
5.7033 0 Td
(incubation)Tj
4.6147 0 Td
(of)Tj
1.0319 0 Td
(striatal)Tj
2.982 0 Td
(cells)Tj
1.9559 0 Td
(from)Tj
-34.9736 -1.3039 Td
(Hdh111Q)Tj
4.2632 0 Td
(mice)Tj
2.1827 0 Td
(in)Tj
1.0488 0 Td
(metformin)Tj
4.6261 0 Td
(reduced)Tj
3.4979 0 Td
(cell)Tj
1.5874 0 Td
(death)Tj
2.4662 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
1.627 0 Td
(Finally,)Tj
3.2258 0 Td
(in)Tj
1.0488 0 Td
(the)Tj
/F7 1 Tf
1.4911 0 Td
[()12()]TJ
1.0318 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8481 0 Td
(R6/2)Tj
2.1487 0 Td
(mouse)Tj
2.8913 0 Td
(model)Tj
-34.9849 -1.2982 Td
(of)Tj
1.0262 0 Td
(HD,)Tj
1.9728 0 Td
(male)Tj
2.1713 0 Td
(mice)Tj
2.1827 0 Td
(treated)Tj
3.0444 0 Td
(with)Tj
2.0239 0 Td
(metformin)Tj
4.6261 0 Td
(had)Tj
1.7291 0 Td
(a)Tj
0.6633 0 Td
(significantly)Tj
5.1817 0 Td
(prolonged)Tj
4.3937 0 Td
(survival)Tj
3.3959 0 Td
(time)Tj
2.0522 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
1.6328 0 Td
(In)Tj
-36.0961 -1.2983 Td
(contrast,)Tj
3.7473 0 Td
(over)Tj
2.0069 0 Td
(activated)Tj
3.8438 0 Td
(forms)Tj
2.6022 0 Td
(of)Tj
1.0261 0 Td
(AMPK)Tj
3.0614 0 Td
(have)Tj
2.0863 0 Td
(been)Tj
2.1486 0 Td
(found)Tj
2.6533 0 Td
(in)Tj
1.0544 0 Td
(brain)Tj
2.3811 0 Td
(tissue)Tj
2.5002 0 Td
(of)Tj
1.0261 0 Td
(HD)Tj
1.7405 0 Td
(patients)Tj
-31.8782 -1.3039 Td
(together)Tj
3.5886 0 Td
(with)Tj
2.0239 0 Td
(data)Tj
1.9446 0 Td
(from)Tj
/F7 1 Tf
2.2336 0 Td
[()12()]TJ
1.0262 0 Td
[()-13()14()7()20()]TJ
/F6 1 Tf
2.0806 0 Td
(and)Tj
/F7 1 Tf
1.7518 0 Td
[()12()]TJ
1.0318 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8482 0 Td
(models)Tj
3.1464 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(])Tj
3.0784 0 Td
(suggest)Tj
3.1691 0 Td
(that)Tj
1.8085 0 Td
(AMPK)Tj
3.0558 0 Td
(activation)Tj
-31.7875 -1.2983 Td
(during)Tj
2.9706 0 Td
(late)Tj
1.6498 0 Td
(stages)Tj
2.6022 0 Td
(of)Tj
1.0318 0 Td
(HD)Tj
1.7348 0 Td
(may)Tj
1.9502 0 Td
(have)Tj
2.0863 0 Td
(deleterious)Tj
4.6771 0 Td
(effects,)Tj
3.0047 0 Td
(so)Tj
1.0999 0 Td
(that)Tj
1.8084 0 Td
(AMPK)Tj
3.0558 0 Td
(may)Tj
1.9502 0 Td
(be)Tj
1.1679 0 Td
(best)Tj
1.8368 0 Td
(considered)Tj
-32.6265 -1.2982 Td
(as)Tj
1.0262 0 Td
(a)Tj
0.6632 0 Td
(target)Tj
2.5511 0 Td
(to)Tj
1.0375 0 Td
(treat)Tj
2.0806 0 Td
(HD)Tj
1.7405 0 Td
(during)Tj
2.9707 0 Td
(early)Tj
2.1826 0 Td
(phases)Tj
2.8857 0 Td
(of)Tj
1.0318 0 Td
(the)Tj
1.491 0 Td
(disease.)Tj
-0.004 Tc
-18.4647 -1.2983 Td
(Cognitive)Tj
4.1158 0 Td
(deterioration)Tj
5.4652 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1508 0 Td
(used)Tj
2.058 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6576 0 Td
(hallmark)Tj
3.7927 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(progression)Tj
4.9209 0 Td
(of)Tj
1.0148 0 Td
(HD)Tj
1.7234 0 Td
(pathology,)Tj
4.405 0 Td
(and)Tj
-35.6255 -1.3039 Td
(hence)Tj
2.5681 0 Td
(any)Tj
1.6554 0 Td
(observed)Tj
3.7928 0 Td
(improvements)Tj
6.0321 0 Td
(in)Tj
1.0374 0 Td
(cognitive)Tj
3.8721 0 Td
(symptoms)Tj
4.3597 0 Td
(after)Tj
2.0352 0 Td
(a)Tj
0.6577 0 Td
(given)Tj
2.3754 0 Td
(treatment)Tj
4.1386 0 Td
(should)Tj
-32.5245 -1.2983 Td
(reflect)Tj
2.6928 0 Td
(some)Tj
2.3301 0 Td
(degree)Tj
2.8573 0 Td
(of)Tj
1.0148 0 Td
(neuronal)Tj
3.8267 0 Td
(protection.)Tj
4.6035 0 Td
(Based)Tj
2.5511 0 Td
(on)Tj
1.2756 0 Td
(our)Tj
1.6214 0 Td
(previously)Tj
4.354 0 Td
(published)Tj
4.1216 0 Td
(data)Tj
1.9162 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(],)Tj
2.0749 0 Td
(we)Tj
-35.24 -1.2983 Td
(hypothesized)Tj
5.4651 0 Td
(that)Tj
1.7801 0 Td
(metformin)Tj
4.5638 0 Td
(intake)Tj
2.6872 0 Td
(might)Tj
2.5965 0 Td
(ameliorate)Tj
4.4447 0 Td
(neuronal)Tj
3.8268 0 Td
(function,)Tj
3.8551 0 Td
(and)Tj
1.7291 0 Td
(by)Tj
1.1849 0 Td
(extension)Tj
-32.1333 -1.3039 Td
(reduce)Tj
2.9139 0 Td
(cognitive)Tj
3.8778 0 Td
(decline,)Tj
3.3052 0 Td
(in)Tj
1.0375 0 Td
(HD)Tj
1.7234 0 Td
(patients.)Tj
3.5943 0 Td
(A)Tj
0.9014 0 Td
(significant)Tj
4.388 0 Td
(number)Tj
3.4186 0 Td
(of)Tj
1.0148 0 Td
(HD)Tj
1.7234 0 Td
(patients,)Tj
3.5944 0 Td
(also)Tj
1.7688 0 Td
(suffering)Tj
-33.2615 -1.2982 Td
(from)Tj
2.2053 0 Td
(type)Tj
1.9105 0 Td
(2)Tj
0.6973 0 Td
(diabetes,)Tj
3.6907 0 Td
(have)Tj
2.058 0 Td
(been)Tj
2.1203 0 Td
(prescribed)Tj
4.4163 0 Td
(metformin.)Tj
4.7849 0 Td
(This)Tj
1.9899 0 Td
(data)Tj
1.9105 0 Td
(is)Tj
0.8504 0 Td
(available)Tj
3.668 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(Enroll-HD)Tj
-32.8079 -1.2983 Td
(cohort,)Tj
3.0783 0 Td
(which)Tj
2.6533 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
0.6519 0 Td
(worldwide)Tj
4.4617 0 Td
(observational)Tj
5.5786 0 Td
(study)Tj
2.3924 0 Td
(on)Tj
1.2756 0 Td
(HD.)Tj
1.9446 0 Td
(We)Tj
1.61 0 Td
(therefore)Tj
3.8551 0 Td
(explored)Tj
3.702 0 Td
(the)Tj
1.4684 0 Td
(existence)Tj
-33.5166 -1.3039 Td
(of)Tj
1.0148 0 Td
(an)Tj
1.2018 0 Td
(association)Tj
4.6261 0 Td
(between)Tj
3.532 0 Td
(metformin)Tj
4.5637 0 Td
(intake)Tj
2.6873 0 Td
(and)Tj
1.7291 0 Td
(cognitive)Tj
3.8721 0 Td
(performance)Tj
5.3518 0 Td
(in)Tj
1.0318 0 Td
(HD)Tj
1.7234 0 Td
(individuals)Tj
4.6488 0 Td
(by)Tj
-35.9827 -1.2983 Td
(analyzing)Tj
4.0251 0 Td
(the)Tj
1.4627 0 Td
(Enroll-HD)Tj
4.5524 0 Td
(by)Tj
1.1735 0 Td
(statistical)Tj
3.9061 0 Td
(means.)Tj
3.0218 0 Td
(Using)Tj
2.5908 0 Td
(linear)Tj
2.5058 0 Td
(regression)Tj
4.3087 0 Td
(models)Tj
3.101 0 Td
(we)Tj
1.321 0 Td
(have)Tj
2.0522 0 Td
(observed)Tj
-34.0211 -1.2983 Td
(an)Tj
1.2018 0 Td
(association)Tj
4.6261 0 Td
(between)Tj
3.532 0 Td
(metformin)Tj
4.5637 0 Td
(use)Tj
1.5307 0 Td
(and)Tj
1.7292 0 Td
(better)Tj
2.5398 0 Td
(cognitive)Tj
3.8777 0 Td
(results)Tj
2.8063 0 Td
(in)Tj
1.0375 0 Td
(different)Tj
3.6567 0 Td
(cognitive)Tj
3.8721 0 Td
(test,)Tj
-34.9736 -1.2982 Td
(suggesting)Tj
4.3993 0 Td
(that)Tj
1.7801 0 Td
(metformin)Tj
4.5638 0 Td
(may)Tj
1.9275 0 Td
(improve)Tj
3.583 0 Td
(cognitive)Tj
3.8721 0 Td
(symptoms)Tj
4.3597 0 Td
(in)Tj
1.0374 0 Td
(HD)Tj
1.7235 0 Td
(patients.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 325.9842 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F0 1 Tf
0 -1.4976 Td
(Clinical)Tj
3.3874 0 Td
(characteristics)Tj
6.5386 0 Td
(of)Tj
1.0488 0 Td
(the)Tj
1.5922 0 Td
(sample)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 291.0047 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Enroll-HD)Tj
4.5637 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
0.6577 0 Td
(world-wide)Tj
4.8075 0 Td
(observational)Tj
5.5785 0 Td
(study)Tj
2.3925 0 Td
(on)Tj
1.2755 0 Td
(HD)Tj
1.7235 0 Td
(which)Tj
2.6475 0 Td
(derives)Tj
3.0501 0 Td
(from)Tj
2.2053 0 Td
(the)Tj
1.4684 0 Td
(integration)Tj
4.6488 0 Td
(of)Tj
-35.8637 -1.2982 Td
(two)Tj
1.7064 0 Td
(existing)Tj
3.3165 0 Td
(HD)Tj
1.7235 0 Td
(observational)Tj
5.5785 0 Td
(studies:)Tj
3.2145 0 Td
(REGISTRY)Tj
4.8075 0 Td
(\(Europe\))Tj
3.8154 0 Td
(and)Tj
1.7291 0 Td
(COHORT)Tj
4.3767 0 Td
(\(North)Tj
3.0047 0 Td
(America)Tj
-33.2728 -1.3039 Td
(and)Tj
1.7291 0 Td
(Australia\).)Tj
4.4107 0 Td
(The)Tj
1.7801 0 Td
(database)Tj
3.6397 0 Td
(includes)Tj
3.5432 0 Td
(in-depth)Tj
3.6851 0 Td
(clinical)Tj
3.0727 0 Td
(records)Tj
3.2088 0 Td
(which)Tj
2.6475 0 Td
(are)Tj
1.4514 0 Td
(collected)Tj
3.736 0 Td
(following)Tj
-32.9043 -1.2983 Td
(finely)Tj
2.4491 0 Td
(stablished)Tj
4.1725 0 Td
(methods,)Tj
3.9062 0 Td
(so)Tj
1.0885 0 Td
(the)Tj
1.474 0 Td
(records)Tj
3.2031 0 Td
(form)Tj
2.2053 0 Td
(different)Tj
3.6567 0 Td
(hospitals)Tj
3.7417 0 Td
(and)Tj
1.7291 0 Td
(countries)Tj
3.9458 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1509 0 Td
(treated)Tj
-34.35 -1.2983 Td
(homogeneously.)Tj
6.7634 0 Td
(The)Tj
1.7801 0 Td
(database)Tj
3.6397 0 Td
(cohort)Tj
2.8573 0 Td
(includes)Tj
3.5433 0 Td
(HD)Tj
1.7234 0 Td
(patients)Tj
3.3676 0 Td
(disease)Tj
3.0217 0 Td
(together)Tj
3.5319 0 Td
(with)Tj
1.9956 0 Td
(pre-manifest)Tj
-32.224 -1.3039 Td
(carriers)Tj
3.2428 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(mutant)Tj
3.1464 0 Td
(allele)Tj
2.2394 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
/F7 1 Tf
1.4683 0 Td
[()22()]TJ
/F6 1 Tf
1.3266 0 Td
(gene)Tj
2.0806 0 Td
(\(people)Tj
3.1918 0 Td
(with)Tj
2.0013 0 Td
(36)Tj
1.1679 0 Td
(or)Tj
1.0998 0 Td
(more)Tj
2.3414 0 Td
(CAG)Tj
2.2847 0 Td
(triplets\),)Tj
3.566 0 Td
(and)Tj
1.7291 0 Td
(con-)Tj
-34.384 -1.2982 Td
(trols.)Tj
2.228 0 Td
(This)Tj
1.9842 0 Td
(database)Tj
3.6397 0 Td
(also)Tj
1.7688 0 Td
(contains)Tj
3.6113 0 Td
(detailed)Tj
3.3675 0 Td
(information)Tj
5.074 0 Td
(about)Tj
2.4945 0 Td
(educational)Tj
4.8585 0 Td
(status,)Tj
2.727 0 Td
(drug)Tj
2.1089 0 Td
(abuse)Tj
-33.8624 -1.2983 Td
(habits,)Tj
2.8402 0 Td
(health)Tj
2.6759 0 Td
(conditions)Tj
4.4787 0 Td
(\(others)Tj
3.0444 0 Td
(than)Tj
2.0296 0 Td
(HD\),)Tj
2.2904 0 Td
(medication)Tj
4.7338 0 Td
(etc.)Tj
1.5931 0 Td
(Regarding)Tj
4.3426 0 Td
(HD,)Tj
1.9503 0 Td
(Enroll-HD)Tj
4.5637 0 Td
(con-)Tj
-34.5427 -1.3039 Td
(tains)Tj
2.1259 0 Td
(a)Tj
0.6577 0 Td
(wide)Tj
2.1203 0 Td
(range)Tj
2.4604 0 Td
(of)Tj
1.0148 0 Td
(motor)Tj
2.7269 0 Td
(and)Tj
1.7291 0 Td
(cognitive)Tj
3.8721 0 Td
(tests.)Tj
2.1884 0 Td
(We)Tj
1.61 0 Td
(have)Tj
2.058 0 Td
(analyzed)Tj
3.702 0 Td
(on)Tj
1.2756 0 Td
(a)Tj
0.6576 0 Td
(cohort)Tj
2.8517 0 Td
(of)Tj
1.0148 0 Td
(Enroll-HD)Tj
-32.0653 -1.2983 Td
(manifest)Tj
3.6566 0 Td
(HD)Tj
1.7235 0 Td
(patients)Tj
3.3732 0 Td
(using)Tj
2.3867 0 Td
(linear)Tj
2.5115 0 Td
(models,)Tj
3.3279 0 Td
(to)Tj
1.0261 0 Td
(compare)Tj
3.719 0 Td
(cognitive)Tj
3.8721 0 Td
(function)Tj
3.6284 0 Td
(between)Tj
3.5319 0 Td
(users)Tj
2.262 0 Td
(and)Tj
-35.0189 -1.2983 Td
(non-users)Tj
4.2179 0 Td
(of)Tj
1.0148 0 Td
(metformin.)Tj
-4.0365 -1.2982 Td
(Our)Tj
1.8708 0 Td
(sample)Tj
3.0217 0 Td
(consisted)Tj
3.9345 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(set)Tj
1.3039 0 Td
(of)Tj
1.0148 0 Td
(7000)Tj
2.126 0 Td
(individuals)Tj
4.6487 0 Td
(from)Tj
2.2054 0 Td
(the)Tj
1.4683 0 Td
(Enroll-HD)Tj
4.5638 0 Td
(cohort)Tj
2.8516 0 Td
(\(those)Tj
2.6816 0 Td
(who)Tj
-34.5541 -1.3039 Td
(had)Tj
1.7064 0 Td
(their)Tj
2.109 0 Td
(pharmacologic)Tj
6.1624 0 Td
(treatments)Tj
4.4958 0 Td
(registered\).)Tj
4.7224 0 Td
(Of)Tj
1.253 0 Td
(these,)Tj
2.4774 0 Td
(4345)Tj
2.126 0 Td
(\(62.1%\))Tj
3.3052 0 Td
(were)Tj
2.1259 0 Td
(manifest)Tj
3.6567 0 Td
(HD,)Tj
-34.1402 -1.2983 Td
(1271)Tj
2.1203 0 Td
(\(18.2%\))Tj
3.3108 0 Td
(were)Tj
2.1203 0 Td
(pre-manifest)Tj
5.3234 0 Td
(and)Tj
1.7292 0 Td
(the)Tj
1.474 0 Td
(remaining)Tj
4.3653 0 Td
(1384)Tj
2.1203 0 Td
(\(19.7%\))Tj
3.3108 0 Td
(were)Tj
2.1203 0 Td
(controls.)Tj
3.7077 0 Td
(7.4%)Tj
2.1543 0 Td
(of)Tj
-33.8567 -1.2983 Td
(controls)Tj
3.4809 0 Td
(and)Tj
1.7291 0 Td
(2.8%)Tj
2.1543 0 Td
(of)Tj
1.0148 0 Td
(HD)Tj
1.7235 0 Td
(patients)Tj
3.3675 0 Td
(were)Tj
2.126 0 Td
(prescribed)Tj
4.4107 0 Td
(metformin)Tj
4.5637 0 Td
(to)Tj
1.0261 0 Td
(treat)Tj
2.0466 0 Td
(their)Tj
2.109 0 Td
(type)Tj
1.9105 0 Td
(2)Tj
0.6974 0 Td
(diabetic)Tj
3.3675 0 Td
(con-)Tj
-35.7276 -1.3039 Td
(dition,)Tj
2.8573 0 Td
(which)Tj
2.6532 0 Td
(is)Tj
0.8504 0 Td
(independent)Tj
5.2724 0 Td
(of)Tj
1.0148 0 Td
(HD.)Tj
1.9502 0 Td
(Insulin-dependent)Tj
7.6478 0 Td
(diabetics)Tj
3.7304 0 Td
(do)Tj
1.2529 0 Td
(not)Tj
1.576 0 Td
(regularly)Tj
3.7588 0 Td
(use)Tj
1.5307 0 Td
(metfor-)Tj
-34.0949 -1.2982 Td
(min)Tj
1.8538 0 Td
(and)Tj
1.7291 0 Td
(their)Tj
2.109 0 Td
(pathology)Tj
4.1782 0 Td
(has)Tj
1.5421 0 Td
(different)Tj
3.6566 0 Td
(molecular)Tj
4.218 0 Td
(basis)Tj
2.1486 0 Td
(than)Tj
2.0296 0 Td
(type)Tj
1.9162 0 Td
(2)Tj
0.6917 0 Td
(diabetes,)Tj
3.6906 0 Td
(so)Tj
1.0885 0 Td
(they)Tj
1.9219 0 Td
(were)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 451.8992 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Metformin)Tj
4.5992 0 Td
(and)Tj
1.8567 0 Td
(Huntingto)Tj
4.1953 0 Td
(n's)Tj
1.474 0 Td
(disease)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.01792)Tj
4.089 0 Td
(83)Tj
0 g
2.0906 0 Td
(June)Tj
2.3528 0 Td
(20,)Tj
1.5874 0 Td
(2017)Tj
34.9656 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(11)Tj
ET
Q
q
0.83 0.64 0.02 0 k
1 j
1 J
0 w
79.5969 663.6472 m
186.0661 663.6472 l
h
f*
36 652.6488 m
171.5528 652.6488 l
h
f*
36 641.6504 m
132.8315 641.6504 l
h
f*
130.6772 443.622 m
183.515 443.622 l
h
f*
36 432.6236 m
112.1953 432.6236 l
h
f*
121.3795 388.6299 m
185.3291 388.6299 l
h
f*
36 377.6315 m
43.1433 377.6315 l
h
f*
0 g
7.9999 0 0 7.9999 36 708.7181 cm
BT
/F10 1 Tf
1 TL
-0.025 Tc
0 0 Td
(retrieve)Tj
2.9693 0 Td
(the)Tj
1.3677 0 Td
(coded)Tj
2.4874 0 Td
(Enroll-HD)Tj
3.8126 0 Td
(data)Tj
1.793 0 Td
(files)Tj
1.7079 0 Td
(using)Tj
2.2535 0 Td
(an)Tj
-16.3914 -1.3748 Td
(encryptio)Tj
3.437 0 Td
(n)Tj
0.6945 0 Td
(key.)Tj
1.7079 0 Td
(The)Tj
1.5945 0 Td
(recipien)Tj
2.8984 0 Td
(t)Tj
0.4748 0 Td
(research/org)Tj
4.7056 0 Td
(anization)Tj
-15.5127 -1.3748 Td
(must)Tj
2.126 0 Td
(agree)Tj
2.2606 0 Td
(\(electronically\))Tj
5.6481 0 Td
(to)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(Enroll-HD)Tj
3.8197 0 Td
(data)Tj
-16.1717 -1.3748 Td
(use)Tj
1.5378 0 Td
(agreement)Tj
3.9472 0 Td
(-)Tj
0.5244 0 Td
(a)Tj
0.6449 0 Td
(template)Tj
3.4158 0 Td
(of)Tj
0.9496 0 Td
(this)Tj
1.5591 0 Td
(agreement)Tj
4.174 0 Td
(is)Tj
-16.7528 -1.3748 Td
(available)Tj
3.3803 0 Td
(here:)Tj
0.83 0.64 0.02 0 k
2.0693 0 Td
(https://ww)Tj
3.8906 0 Td
(w.enroll-hd.)Tj
4.4008 0 Td
(org/enrollhd_)Tj
-13.741 -1.3748 Td
(documents/)Tj
4.422 0 Td
(Enroll-HD_)Tj
4.0678 0 Td
(DataUseAgr)Tj
4.4221 0 Td
(eement_E-)Tj
-12.9119 -1.3748 Td
(Version_Re)Tj
4.2945 0 Td
(vNo002\(08121)Tj
5.5772 0 Td
(6\).pdf)Tj
0 g
2.4307 0 Td
(Enroll-HD)Tj
3.8126 0 Td
(is)Tj
0.8363 0 Td
(a)Tj
-16.9513 -1.3748 Td
(clinical)Tj
2.7283 0 Td
(research)Tj
3.4158 0 Td
(platform)Tj
3.352 0 Td
(intended)Tj
3.4087 0 Td
(to)Tj
0.9496 0 Td
(accelerat)Tj
3.2811 0 Td
(e)Tj
-17.1355 -1.3749 Td
(progress)Tj
3.522 0 Td
(towards)Tj
3.2103 0 Td
(the)Tj
1.3677 0 Td
(development)Tj
5.0032 0 Td
(of)Tj
0.9496 0 Td
(therapeuti)Tj
3.6922 0 Td
(cs)Tj
-17.745 -1.3748 Td
(that)Tj
1.6228 0 Td
(will)Tj
1.4386 0 Td
(benefit)Tj
2.7142 0 Td
(HD-affecte)Tj
3.9331 0 Td
(d)Tj
0.6945 0 Td
(individuals.)Tj
4.3795 0 Td
(Towards)Tj
-14.7827 -1.3748 Td
(that)Tj
1.6228 0 Td
(goal,)Tj
2.0055 0 Td
(code-protect)Tj
4.7056 0 Td
(ed)Tj
1.1197 0 Td
(clinical)Tj
2.7283 0 Td
(data)Tj
1.793 0 Td
(and)Tj
-13.9749 -1.3748 Td
(biosamples)Tj
4.4646 0 Td
(collected)Tj
3.4937 0 Td
(from)Tj
2.0126 0 Td
(Enroll-HD)Tj
3.8126 0 Td
(participants)Tj
-13.7835 -1.3748 Td
(are)Tj
1.3677 0 Td
(made)Tj
2.2961 0 Td
(available)Tj
3.3732 0 Td
(at)Tj
0.9 0 Td
(periodic)Tj
3.1748 0 Td
(intervals)Tj
3.3308 0 Td
(and)Tj
1.5874 0 Td
(are)Tj
-16.03 -1.3748 Td
(intended)Tj
3.4016 0 Td
(to)Tj
0.9496 0 Td
(energize)Tj
3.2953 0 Td
(HD)Tj
1.396 0 Td
(research)Tj
3.4158 0 Td
(and)Tj
1.5874 0 Td
(encourage)Tj
4.1032 0 Td
(a)Tj
-18.1489 -1.3748 Td
(broad)Tj
2.3669 0 Td
(variety)Tj
2.6646 0 Td
(of)Tj
0.9496 0 Td
(ideas)Tj
2.1473 0 Td
(and)Tj
1.5874 0 Td
(projects.)Tj
3.4157 0 Td
(Present)Tj
2.8205 0 Td
(ly,)Tj
-15.952 -1.3749 Td
(Enroll-HD)Tj
3.8126 0 Td
(study)Tj
2.2677 0 Td
(currently)Tj
3.4937 0 Td
(has)Tj
1.5378 0 Td
(no)Tj
1.1693 0 Td
(defined)Tj
2.9268 0 Td
(end)Tj
1.5875 0 Td
(date)Tj
-16.7954 -1.3748 Td
(and)Tj
1.5874 0 Td
(the)Tj
1.3677 0 Td
(next)Tj
1.7929 0 Td
(planned)Tj
3.1536 0 Td
(periodic)Tj
3.1748 0 Td
(release)Tj
2.8276 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(dataset)Tj
-16.2213 -1.3748 Td
(is)Tj
0.8362 0 Td
(estimate)Tj
3.1394 0 Td
(d)Tj
0.6945 0 Td
(for)Tj
1.2543 0 Td
(2018.)Tj
2.3386 0 Td
(Note:)Tj
2.1827 0 Td
(a)Tj
0.6449 0 Td
(subset)Tj
2.6858 0 Td
(of)Tj
0.9497 0 Td
(the)Tj
1.3677 0 Td
(data)Tj
1.7929 0 Td
(is)Tj
-17.8867 -1.3819 Td
(not)Tj
1.4244 0 Td
(routinel)Tj
2.785 0 Td
(y)Tj
0.6449 0 Td
(made)Tj
2.289 0 Td
(available)Tj
3.3804 0 Td
(through)Tj
3.1535 0 Td
(the)Tj
1.3678 0 Td
(periodic)Tj
-15.045 -1.3748 Td
(dataset)Tj
2.8913 0 Td
(releases;)Tj
3.4725 0 Td
(to)Tj
0.9496 0 Td
(request)Tj
2.9906 0 Td
(access)Tj
2.7496 0 Td
(to)Tj
0.9496 0 Td
(these)Tj
-14.0032 -1.3748 Td
(datasets,)Tj
3.5362 0 Td
(there)Tj
2.0977 0 Td
(is)Tj
0.8362 0 Td
(a)Tj
0.6378 0 Td
(more)Tj
2.1756 0 Td
(rigorous)Tj
3.3449 0 Td
(process)Tj
3.1607 0 Td
(in)Tj
0.8858 0 Td
(place,)Tj
-16.6749 -1.3748 Td
(necessitate)Tj
4.1244 0 Td
(d)Tj
0.6945 0 Td
(by)Tj
1.1197 0 Td
(the)Tj
1.3677 0 Td
(fact)Tj
1.5732 0 Td
(that)Tj
1.6229 0 Td
(these)Tj
2.2181 0 Td
(data)Tj
1.793 0 Td
(may)Tj
1.8141 0 Td
(be)Tj
-16.3276 -1.3748 Td
(more)Tj
2.1756 0 Td
(sensitive)Tj
3.4441 0 Td
(and)Tj
1.5874 0 Td
(could)Tj
2.2536 0 Td
(increase)Tj
3.3023 0 Td
(potential)Tj
-12.763 -1.3749 Td
(identification)Tj
4.9181 0 Td
(risk.)Tj
1.7858 0 Td
(The)Tj
1.5875 0 Td
(Enroll-HD)Tj
3.8197 0 Td
(Scientifi)Tj
2.9268 0 Td
(c)Tj
-15.0379 -1.3748 Td
(Publication/)Tj
4.3512 0 Td
(Review)Tj
2.9055 0 Td
(Committe)Tj
3.6284 0 Td
(e)Tj
0.6449 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(http://docs)Tj
4.2874 0 Td
(.enroll-)Tj
-15.8174 -1.3748 Td
(hd.org/htm)Tj
4.1598 0 Td
(l/wg/pub_co)Tj
4.6064 0 Td
(m)Tj
0 g
(\))Tj
1.2826 0 Td
(reviews)Tj
3.0473 0 Td
(each)Tj
1.9559 0 Td
(request)Tj
-15.052 -1.3748 Td
(on)Tj
1.1693 0 Td
(a)Tj
0.6378 0 Td
(case)Tj
1.9063 0 Td
(by)Tj
1.1126 0 Td
(case)Tj
1.9063 0 Td
(basis)Tj
2.1543 0 Td
(and)Tj
1.5874 0 Td
(carefully)Tj
3.3308 0 Td
(assess)Tj
2.5228 0 Td
(es)Tj
1.063 0 Td
(the)Tj
-17.3906 -1.3748 Td
(scientific)Tj
3.4724 0 Td
(merit)Tj
2.1473 0 Td
(of)Tj
0.9496 0 Td
(a)Tj
0.6378 0 Td
(proposal)Tj
3.4583 0 Td
(against)Tj
2.8843 0 Td
(the)Tj
1.3677 0 Td
(potential)Tj
-14.9174 -1.3748 Td
(risk)Tj
1.5661 0 Td
(of)Tj
0.9425 0 Td
(identification.)Tj
5.145 0 Td
(The)Tj
1.5874 0 Td
(main)Tj
2.0622 0 Td
(contact)Tj
2.941 0 Td
(for)Tj
1.2543 0 Td
(this)Tj
-15.4985 -1.3748 Td
(committee)Tj
4.1669 0 Td
(is)Tj
0.8362 0 Td
(Olivia)Tj
2.2323 0 Td
(Handley:)Tj
0.83 0.64 0.02 0 k
3.4371 0 Td
(HandleyO@)Tj
4.3512 0 Td
(cardiff.ac.)Tj
-15.0237 -1.3749 Td
(uk)Tj
0 g
(.)Tj
/F9 1 Tf
0 -2.126 Td
(Funding:)Tj
/F10 1 Tf
3.5716 0 Td
(RVM)Tj
2.0835 0 Td
(holds)Tj
2.2607 0 Td
(a)Tj
0.6378 0 Td
(Miguel)Tj
3.0897 0 Td
(Servet)Tj
2.9268 0 Td
(fellowship)Tj
-14.5701 -1.3748 Td
(\(Ref:)Tj
2.0126 0 Td
(CP11/00090)Tj
4.6205 0 Td
(\))Tj
0.5315 0 Td
(funded)Tj
2.7921 0 Td
(by)Tj
1.1126 0 Td
(the)Tj
1.3678 0 Td
(Instituto)Tj
3.2811 0 Td
(de)Tj
1.1126 0 Td
(Salud)Tj
-16.8308 -1.3748 Td
(Carlos)Tj
2.5653 0 Td
(III)Tj
0.9851 0 Td
(\(ISCIII,)Tj
2.8205 0 Td
(Madrid,)Tj
3.0685 0 Td
(Spain\),)Tj
2.8347 0 Td
(a)Tj
0.6448 0 Td
(grant)Tj
2.1473 0 Td
(from)Tj
2.0126 0 Td
(the)Tj
-17.0788 -1.3748 Td
(ISCIII)Tj
2.2889 0 Td
(\(PI14/00949\))Tj
5.1875 0 Td
(and)Tj
1.5874 0 Td
(Fundacio)Tj
0 Tc
2.9622 0.0354 Td
()Tj
-0.025 Tc
0.6095 -0.0354 Td
(Telemarato)Tj
0 Tc
3.7488 0.0354 Td
()Tj
-0.025 Tc
0.6166 -0.0354 Td
(de)Tj
1.1126 0 Td
(la)Tj
-18.1135 -1.3748 Td
(TV3)Tj
1.6937 0 Td
(\(ref:)Tj
1.7362 0 Td
(559\).)Tj
2.1685 0 Td
(The)Tj
1.5874 0 Td
(funds)Tj
2.3174 0 Td
(from)Tj
2.0126 0 Td
(the)Tj
1.3677 0 Td
(ISCIII)Tj
2.2961 0 Td
(are)Tj
-15.1796 -1.3748 Td
(partially)Tj
3.0968 0 Td
(supported)Tj
3.9969 0 Td
(by)Tj
1.1126 0 Td
(the)Tj
1.3677 0 Td
(European)Tj
3.7418 0 Td
(Regional)Tj
-13.3158 -1.3748 Td
(Developmen)Tj
4.6417 0 Td
(t)Tj
0.4748 0 Td
(Fund.)Tj
2.2819 0 Td
(RVM)Tj
2.0906 0 Td
(is)Tj
0.8362 0 Td
(also)Tj
1.7292 0 Td
(a)Tj
0.6378 0 Td
(Marie)Tj
2.3173 0 Td
(Curie)Tj
-15.0095 -1.3749 Td
(fellow)Tj
2.3952 0 Td
(\(CIG322034)Tj
4.5143 0 Td
(,)Tj
0.4464 0 Td
(EU\).)Tj
1.8142 0 Td
(The)Tj
1.5874 0 Td
(funders)Tj
3.0473 0 Td
(had)Tj
1.5874 0 Td
(no)Tj
1.1622 0 Td
(role)Tj
1.6158 0 Td
(in)Tj
-18.1702 -1.3748 Td
(study)Tj
2.2677 0 Td
(design,)Tj
2.8984 0 Td
(data)Tj
1.793 0 Td
(collection)Tj
3.7346 0 Td
(and)Tj
1.5874 0 Td
(analysis,)Tj
3.4158 0 Td
(decision)Tj
-15.6969 -1.3748 Td
(to)Tj
0.9496 0 Td
(publish,)Tj
3.1464 0 Td
(or)Tj
0.9993 0 Td
(preparation)Tj
4.4433 0 Td
(of)Tj
0.9425 0 Td
(the)Tj
1.3748 0 Td
(manuscript.)Tj
/F9 1 Tf
-11.8559 -2.126 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F10 1 Tf
0.4819 0 Td
(The)Tj
1.5875 0 Td
(authors)Tj
3.0401 0 Td
(have)Tj
1.963 0 Td
(declared)Tj
-14.7827 -1.3748 Td
(that)Tj
1.6228 0 Td
(no)Tj
1.1693 0 Td
(competing)Tj
4.1599 0 Td
(interests)Tj
ET
endstream
endobj
46 0 obj
<>stream
endstream
endobj
47 0 obj
<>stream
endstream
endobj
48 0 obj
<>stream
endstream
endobj
49 0 obj
<>stream
endstream
endobj
50 0 obj
<>stream
endstream
endobj
51 0 obj
<>stream
endstream
endobj
52 0 obj
<>stream
endstream
endobj
53 0 obj
<>stream
endstream
endobj
54 0 obj
<>stream
endstream
endobj
55 0 obj
<>stream
endstream
endobj
56 0 obj
<>stream
BT
10.3394 -59.2516 Td
(exist.)Tj
ET
Q
endstream
endobj
57 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 59 0 R/Contents 60 0 R/TrimBox[0 0 612 792]>>
endobj
59 0 obj
[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]
endobj
61 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref017)>>
endobj
62 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.t001)>>
endobj
63 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.t001)>>
endobj
64 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.t002)>>
endobj
65 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.t002)>>
endobj
66 0 obj
<>/Border[0 0 0]/A 72 0 R>>
endobj
72 0 obj
<>
endobj
67 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.ref018)>>
endobj
68 0 obj
<>/Border[0 0 0]/Dest(Rpone.0179283.t002)>>
endobj
69 0 obj
<>/Border[0 0 0]/Dest(Lpone.0179283.t001)>>
endobj
70 0 obj
<>/Border[0 0 0]/A 73 0 R>>
endobj
73 0 obj
<>
endobj
71 0 obj
<>/Border[0 0 0]/A 74 0 R>>
endobj
74 0 obj
<>
endobj
60 0 obj
[75 0 R 76 0 R 77 0 R 78 0 R 79 0 R 80 0 R 81 0 R]
endobj
75 0 obj
<>stream
q
0.83 0.64 0.02 0 k
203.4142 680.315 m
212.9386 680.315 l
h
f*
505.4173 654.3496 m
534.6142 654.3496 l
h
f*
239.1307 628.3276 m
268.2709 628.3276 l
h
f*
415.0488 602.3055 m
444.189 602.3055 l
h
f*
259.937 589.3228 m
289.1339 589.3228 l
h
f*
371.622 537.3354 m
397.6441 537.3354 l
h
f*
464.1449 537.3354 m
473.6693 537.3354 l
h
f*
515.9622 511.3134 m
545.1024 511.3134 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(excluded)Tj
3.7813 0 Td
(from)Tj
2.2111 0 Td
(this)Tj
1.6724 0 Td
(analysis.)Tj
3.5489 0 Td
(The)Tj
1.7859 0 Td
(proportions)Tj
4.9889 0 Td
(of)Tj
1.0148 0 Td
(type)Tj
1.9162 0 Td
(2)Tj
0.6973 0 Td
(diabetic)Tj
3.3676 0 Td
(individuals)Tj
4.6487 0 Td
(among)Tj
2.9934 0 Td
(the)Tj
1.4684 0 Td
(groups)Tj
-34.0949 -1.3039 Td
(of)Tj
1.0147 0 Td
(people)Tj
2.8517 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(Enroll-HD)Tj
4.5637 0 Td
(database)Tj
3.6397 0 Td
(were)Tj
2.1203 0 Td
(within)Tj
2.8176 0 Td
(the)Tj
1.4684 0 Td
(expected)Tj
3.719 0 Td
(range)Tj
2.4661 0 Td
(for)Tj
1.3833 0 Td
(Western)Tj
3.6113 0 Td
(populations)Tj
-32.1616 -1.2982 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
2.0692 0 Td
(The)Tj
1.7802 0 Td
(age)Tj
1.5363 0 Td
(profile)Tj
2.8347 0 Td
(of)Tj
1.0091 0 Td
(the)Tj
1.4627 0 Td
(two)Tj
1.7007 0 Td
(groups)Tj
2.9651 0 Td
(\(controls)Tj
3.821 0 Td
(and)Tj
1.7235 0 Td
(patients\))Tj
3.702 0 Td
(was)Tj
1.6951 0 Td
(similar,)Tj
3.2032 0 Td
(although)Tj
3.7473 0 Td
(metformin)Tj
-33.2501 -1.2983 Td
(users)Tj
2.2563 0 Td
(were)Tj
2.1146 0 Td
(510)Tj
2.16 0 Td
(years)Tj
2.2564 0 Td
(older)Tj
2.2904 0 Td
(on)Tj
1.2699 0 Td
(average.)Tj
3.4469 0 Td
(With)Tj
2.2734 0 Td
(respect)Tj
3.033 0 Td
(to)Tj
1.0148 0 Td
(HD's)Tj
2.2961 0 Td
(status,)Tj
2.7212 0 Td
(of)Tj
1.0091 0 Td
(those)Tj
2.3301 0 Td
(carrying)Tj
3.549 0 Td
(a)Tj
0.6462 0 Td
(mutant)Tj
-34.6674 -1.2983 Td
(allele)Tj
2.2393 0 Td
(\(i.e.)Tj
/F12 1 Tf
0 Tc
1.7008 0 Td
(>)Tj
/F6 1 Tf
-0.004 Tc
(35)Tj
1.9445 0 Td
(CAG)Tj
2.2791 0 Td
(triplets\))Tj
3.3448 0 Td
(64.8%)Tj
2.6306 0 Td
(\(4345\))Tj
2.8006 0 Td
(were)Tj
2.126 0 Td
(at)Tj
0.9524 0 Td
(the)Tj
1.4683 0 Td
(motor-manifest)Tj
6.514 0 Td
(stage)Tj
2.1997 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Table)Tj
2.7836 0 Td
(1)Tj
0 g
(\))Tj
1.0318 0 Td
(and)Tj
-34.0155 -1.3039 Td
(were)Tj
2.1203 0 Td
(included)Tj
3.7133 0 Td
(in)Tj
1.0375 0 Td
(our)Tj
1.6214 0 Td
(analysis.)Tj
3.5546 0 Td
(The)Tj
1.7802 0 Td
(average)Tj
3.2258 0 Td
(number)Tj
3.4185 0 Td
(of)Tj
1.0148 0 Td
(CAG)Tj
2.2847 0 Td
(repeats)Tj
3.0501 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(carrier)Tj
2.88 0 Td
(population)Tj
-32.207 -1.2982 Td
(was)Tj
1.6951 0 Td
(43.6)Tj
1.8765 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Table)Tj
2.7779 0 Td
(1)Tj
0 g
(\).)Tj
1.2643 0 Td
(As)Tj
1.2642 0 Td
(expected,)Tj
3.9458 0 Td
(patients)Tj
3.3675 0 Td
(at)Tj
0.9525 0 Td
(the)Tj
1.474 0 Td
(motor-manifest)Tj
6.514 0 Td
(stage)Tj
2.1996 0 Td
(displayed)Tj
3.9798 0 Td
(lower)Tj
2.4492 0 Td
(scores)Tj
2.6702 0 Td
(in)Tj
-36.4306 -1.2983 Td
(all)Tj
1.1451 0 Td
(cognitive)Tj
3.8721 0 Td
(tests)Tj
1.9673 0 Td
(and)Tj
1.7291 0 Td
(also)Tj
1.7688 0 Td
(higher)Tj
2.8006 0 Td
(values)Tj
2.6646 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(UHDRS)Tj
3.5603 0 Td
(motor)Tj
2.7212 0 Td
(score)Tj
2.3074 0 Td
(compared)Tj
4.2463 0 Td
(to)Tj
1.0204 0 Td
(both)Tj
2.0636 0 Td
(carriers)Tj
-34.3726 -1.3039 Td
(at)Tj
0.9524 0 Td
(the)Tj
1.4683 0 Td
(pre-manifest)Tj
5.3235 0 Td
(stage)Tj
2.1996 0 Td
(and)Tj
1.7291 0 Td
(non-carrier)Tj
4.8416 0 Td
(individuals)Tj
4.6488 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Table)Tj
2.7779 0 Td
(2)Tj
0 g
(\).)Tj
1.2643 0 Td
(The)Tj
1.7801 0 Td
(latter)Tj
2.2904 0 Td
(two)Tj
1.7121 0 Td
(groups)Tj
2.9707 0 Td
(showed)Tj
-33.9588 -1.2983 Td
(similar)Tj
2.9876 0 Td
(scores)Tj
2.6646 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Table)Tj
2.7836 0 Td
(2)Tj
0 g
(\).)Tj
1.2586 0 Td
(In)Tj
1.1112 0 Td
(the)Tj
1.4683 0 Td
(control)Tj
3.1237 0 Td
(group,)Tj
2.829 0 Td
(the)Tj
1.474 0 Td
(people)Tj
2.8516 0 Td
(taking)Tj
2.7326 0 Td
(metformin,)Tj
4.7849 0 Td
(to)Tj
1.0261 0 Td
(treat)Tj
2.0466 0 Td
(their)Tj
2.109 0 Td
(type)Tj
-35.2514 -1.2983 Td
(2)Tj
0.6916 0 Td
(diabetic)Tj
3.3732 0 Td
(condition,)Tj
4.337 0 Td
(showed)Tj
3.2541 0 Td
(worse)Tj
2.5625 0 Td
(cognitive)Tj
3.8778 0 Td
(scores)Tj
2.6646 0 Td
(than)Tj
2.0296 0 Td
(non-metformin)Tj
6.5196 0 Td
(users,)Tj
2.4888 0 Td
(which)Tj
2.6475 0 Td
(suggest)Tj
-34.4463 -1.3039 Td
(that)Tj
1.7744 0 Td
(type)Tj
1.9106 0 Td
(2)Tj
0.6916 0 Td
(diabetes)Tj
3.4639 0 Td
(has)Tj
1.5364 0 Td
(negative)Tj
3.5319 0 Td
(consequences)Tj
5.6976 0 Td
(on)Tj
1.2756 0 Td
(cognitive)Tj
3.8721 0 Td
(function)Tj
3.6227 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4626 0 Td
(control)Tj
3.1238 0 Td
(population.)Tj
-33.0007 -1.2982 Td
(This)Tj
1.9842 0 Td
(is)Tj
0.8504 0 Td
(in)Tj
1.0375 0 Td
(agreement)Tj
4.4276 0 Td
(with)Tj
1.9956 0 Td
(previous)Tj
3.651 0 Td
(literature)Tj
3.8778 0 Td
(that)Tj
1.7801 0 Td
(shows)Tj
2.6589 0 Td
(that)Tj
1.7802 0 Td
(type)Tj
1.9162 0 Td
(2)Tj
0.6916 0 Td
(diabetes)Tj
3.4639 0 Td
(has)Tj
1.5421 0 Td
(a)Tj
0.6519 0 Td
(deleterious)Tj
-32.309 -1.2983 Td
(effect)Tj
2.364 0 Td
(over)Tj
1.9786 0 Td
(cognitive)Tj
3.8721 0 Td
(function)Tj
3.6283 0 Td
(\(reviewed)Tj
4.1386 0 Td
(by)Tj
0.83 0.64 0.02 0 k
1.1792 0 Td
(Zilliox)Tj
0 g
2.8176 0 Td
(and)Tj
1.7348 0 Td
(coworkers)Tj
4.3653 0 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(]\).)Tj
2.4151 0 Td
(In)Tj
1.1055 0 Td
(contrast,)Tj
3.6907 0 Td
(amongst)Tj
-33.2898 -1.3039 Td
(HD)Tj
1.7234 0 Td
(patients)Tj
3.3675 0 Td
(who)Tj
1.9389 0 Td
(were)Tj
2.1203 0 Td
(at)Tj
0.9525 0 Td
(the)Tj
1.474 0 Td
(motor)Tj
2.7212 0 Td
(manifest)Tj
3.6567 0 Td
(stage)Tj
2.2053 0 Td
(of)Tj
1.0148 0 Td
(HD,)Tj
1.9502 0 Td
(metformin)Tj
4.5638 0 Td
(users,)Tj
2.4888 0 Td
(which)Tj
2.6475 0 Td
(also)Tj
1.7688 0 Td
(were)Tj
-34.5937 -1.2983 Td
(type)Tj
1.9105 0 Td
(2)Tj
0.6973 0 Td
(diabetics,)Tj
3.9571 0 Td
(had)Tj
1.7065 0 Td
(slightly)Tj
3.0897 0 Td
(better)Tj
2.5399 0 Td
(cognitive)Tj
3.8721 0 Td
(scores)Tj
2.6702 0 Td
(than)Tj
2.0296 0 Td
(non-metformin)Tj
6.514 0 Td
(users)Tj
2.2677 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Table)Tj
2.7836 0 Td
(2)Tj
0 g
(\).)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 486.3685 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(HD)Tj
1.6488 0 Td
(patients)Tj
3.6803 0 Td
(that)Tj
1.8709 0 Td
(take)Tj
2.0929 0 Td
(metformin)Tj
4.6205 0 Td
(show)Tj
2.5276 0 Td
(better)Tj
2.7497 0 Td
(scores)Tj
3.137 0 Td
(in)Tj
0.9827 0 Td
(cognitive)Tj
4.115 0 Td
(tests)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 469.3606 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(In)Tj
1.1055 0 Td
(the)Tj
1.474 0 Td
(Enroll-HD)Tj
4.558 0 Td
(study,)Tj
2.6192 0 Td
(the)Tj
1.4684 0 Td
(assessment)Tj
4.6091 0 Td
(of)Tj
1.0148 0 Td
(cognitive)Tj
3.8777 0 Td
(function)Tj
3.6284 0 Td
(used)Tj
2.0579 0 Td
(specific)Tj
3.1918 0 Td
(neuropsychological)Tj
-29.6048 -1.2982 Td
(tests)Tj
1.9615 0 Td
(to)Tj
1.0261 0 Td
(assess)Tj
2.5172 0 Td
(different)Tj
3.6567 0 Td
(domains)Tj
3.685 0 Td
(of)Tj
1.0148 0 Td
(cognitive)Tj
3.8778 0 Td
(function.)Tj
3.855 0 Td
(Executive)Tj
4.0706 0 Td
(function)Tj
3.6283 0 Td
(was)Tj
1.7008 0 Td
(assessed)Tj
3.4696 0 Td
(using)Tj
-34.4634 -1.3039 Td
(Verbal)Tj
2.8969 0 Td
(Fluency,)Tj
3.5943 0 Td
(Trail)Tj
2.1487 0 Td
(Making)Tj
3.3278 0 Td
(\(Part)Tj
2.2224 0 Td
(B\),)Tj
1.3663 0 Td
(and)Tj
1.7291 0 Td
(Stroop-interference)Tj
8.056 0 Td
(tests.)Tj
2.1884 0 Td
(The)Tj
1.7801 0 Td
(working)Tj
3.5603 0 Td
(memory)Tj
-32.8703 -1.2983 Td
(and)Tj
1.7291 0 Td
(attention)Tj
3.8437 0 Td
(of)Tj
1.0148 0 Td
(patients)Tj
3.3676 0 Td
(and)Tj
1.7291 0 Td
(controls)Tj
3.4866 0 Td
(was)Tj
1.6951 0 Td
(investigated)Tj
4.9889 0 Td
(using)Tj
2.3925 0 Td
(Symbol)Tj
3.2314 0 Td
(Digit)Tj
2.2507 0 Td
(Modalities)Tj
4.4447 0 Td
(Test.)Tj
-34.1742 -1.2983 Td
(Finally,)Tj
3.1691 0 Td
(the)Tj
1.4683 0 Td
(processing)Tj
4.4674 0 Td
(speed)Tj
2.4718 0 Td
(was)Tj
1.7007 0 Td
(checked)Tj
3.464 0 Td
(using)Tj
2.3924 0 Td
(Stroop-Word)Tj
5.6182 0 Td
(Reading)Tj
3.5036 0 Td
(and)Tj
1.7348 0 Td
(Stroop-Colour)Tj
-29.9903 -1.2982 Td
(Naming)Tj
3.4922 0 Td
(tests.)Tj
-2.296 -1.3039 Td
(To)Tj
1.3379 0 Td
(evaluate)Tj
3.4639 0 Td
(the)Tj
1.4684 0 Td
(potential)Tj
3.7643 0 Td
(association)Tj
4.6262 0 Td
(between)Tj
3.5262 0 Td
(use)Tj
1.5364 0 Td
(of)Tj
1.0148 0 Td
(metformin)Tj
4.5638 0 Td
(and)Tj
1.7291 0 Td
(ameliorated)Tj
4.9719 0 Td
(cognitive)Tj
-33.1991 -1.2983 Td
(function)Tj
3.6283 0 Td
(among)Tj
2.9933 0 Td
(HD)Tj
1.7235 0 Td
(patients,)Tj
3.5943 0 Td
(the)Tj
1.4683 0 Td
(optimal)Tj
3.3109 0 Td
(analysis)Tj
3.3278 0 Td
(would)Tj
2.7099 0 Td
(have)Tj
2.0637 0 Td
(consisted)Tj
3.9344 0 Td
(in)Tj
1.0375 0 Td
(comparing)Tj
4.5694 0 Td
(HD)Tj
-34.3613 -1.2983 Td
(individuals)Tj
4.6487 0 Td
(taking)Tj
2.727 0 Td
(metformin)Tj
4.5637 0 Td
(against)Tj
3.0274 0 Td
(HD)Tj
1.7234 0 Td
(individuals)Tj
4.6488 0 Td
(not)Tj
1.5761 0 Td
(taking)Tj
2.7269 0 Td
(metformin.)Tj
4.7905 0 Td
(Unfortunately,)Tj
-30.4325 -1.3039 Td
(this)Tj
1.6724 0 Td
(comparison)Tj
4.9776 0 Td
(was)Tj
1.7008 0 Td
(not)Tj
1.5703 0 Td
(feasible)Tj
3.1692 0 Td
(with)Tj
2.0012 0 Td
(the)Tj
1.4683 0 Td
(Enroll-HD)Tj
4.5638 0 Td
(database)Tj
3.6397 0 Td
(since)Tj
2.2393 0 Td
(both)Tj
2.0636 0 Td
(groups)Tj
2.9707 0 Td
(were)Tj
2.1203 0 Td
(not)Tj
ET
Q
q
0.45 0.36 0.35 0.01 k
1 j
1 J
0 w
36 324.2526 m
576 324.2526 l
576 323.7525 l
36 323.7525 l
f*
79.7267 323.7525 m
79.7267 257.7526 l
79.2266 257.7526 l
79.2266 323.7525 l
f*
79.2266 257.7526 m
36 257.7526 l
36 258.2527 l
79.2266 258.2527 l
f*
329.7917 323.7525 m
329.7917 311.2526 l
329.2917 311.2526 l
329.2917 323.7525 l
f*
329.2917 311.2526 m
79.7267 311.2526 l
79.7267 311.7526 l
329.2917 311.7526 l
f*
576 311.2526 m
329.7917 311.2526 l
329.7917 311.7526 l
576 311.7526 l
f*
203.6183 311.2526 m
203.6183 289.2526 l
203.1182 289.2526 l
203.1182 311.2526 l
f*
203.1182 289.2526 m
79.7267 289.2526 l
79.7267 289.7527 l
203.1182 289.7527 l
f*
329.7917 311.2526 m
329.7917 289.2526 l
329.2917 289.2526 l
329.2917 311.2526 l
f*
329.2917 289.2526 m
203.6183 289.2526 l
203.6183 289.7527 l
329.2917 289.7527 l
f*
454.875 311.2526 m
454.875 289.2526 l
454.375 289.2526 l
454.375 311.2526 l
f*
454.375 289.2526 m
329.7917 289.2526 l
329.7917 289.7527 l
454.375 289.7527 l
f*
576 289.2526 m
454.875 289.2526 l
454.875 289.7527 l
576 289.7527 l
f*
145.4924 289.2526 m
145.4924 257.7526 l
144.9924 257.7526 l
144.9924 289.2526 l
f*
144.9924 257.7526 m
79.7267 257.7526 l
79.7267 258.2527 l
144.9924 258.2527 l
f*
203.6183 289.2526 m
203.6183 257.7526 l
203.1182 257.7526 l
203.1182 289.2526 l
f*
203.1182 257.7526 m
145.4924 257.7526 l
145.4924 258.2527 l
203.1182 258.2527 l
f*
268.2663 289.2526 m
268.2663 257.7526 l
267.7663 257.7526 l
267.7663 289.2526 l
f*
267.7663 257.7526 m
203.6183 257.7526 l
203.6183 258.2527 l
267.7663 258.2527 l
f*
329.7917 289.2526 m
329.7917 257.7526 l
329.2917 257.7526 l
329.2917 289.2526 l
f*
329.2917 257.7526 m
268.2663 257.7526 l
268.2663 258.2527 l
329.2917 258.2527 l
f*
391.6446 289.2526 m
391.6446 257.7526 l
391.1445 257.7526 l
391.1445 289.2526 l
f*
391.1445 257.7526 m
329.7917 257.7526 l
329.7917 258.2527 l
391.1445 258.2527 l
f*
454.875 289.2526 m
454.875 257.7526 l
454.375 257.7526 l
454.375 289.2526 l
f*
454.375 257.7526 m
391.6446 257.7526 l
391.6446 258.2527 l
454.375 258.2527 l
f*
516.7273 289.2526 m
516.7273 257.7526 l
516.2272 257.7526 l
516.2272 289.2526 l
f*
516.2272 257.7526 m
454.875 257.7526 l
454.875 258.2527 l
516.2272 258.2527 l
f*
576 257.7526 m
516.7273 257.7526 l
516.7273 258.2527 l
576 258.2527 l
f*
79.7267 257.7526 m
79.7267 235.7527 l
79.2266 235.7527 l
79.2266 257.7526 l
f*
79.2266 235.7527 m
36 235.7527 l
36 236.2527 l
79.2266 236.2527 l
f*
145.4924 257.7526 m
145.4924 235.7527 l
144.9924 235.7527 l
144.9924 257.7526 l
f*
144.9924 235.7527 m
79.7267 235.7527 l
79.7267 236.2527 l
144.9924 236.2527 l
f*
203.6183 257.7526 m
203.6183 235.7527 l
203.1182 235.7527 l
203.1182 257.7526 l
f*
203.1182 235.7527 m
145.4924 235.7527 l
145.4924 236.2527 l
203.1182 236.2527 l
f*
268.2663 257.7526 m
268.2663 235.7527 l
267.7663 235.7527 l
267.7663 257.7526 l
f*
267.7663 235.7527 m
203.6183 235.7527 l
203.6183 236.2527 l
267.7663 236.2527 l
f*
329.7917 257.7526 m
329.7917 235.7527 l
329.2917 235.7527 l
329.2917 257.7526 l
f*
329.2917 235.7527 m
268.2663 235.7527 l
268.2663 236.2527 l
329.2917 236.2527 l
f*
391.6446 257.7526 m
391.6446 235.7527 l
391.1445 235.7527 l
391.1445 257.7526 l
f*
391.1445 235.7527 m
329.7917 235.7527 l
329.7917 236.2527 l
391.1445 236.2527 l
f*
454.875 257.7526 m
454.875 235.7527 l
454.375 235.7527 l
454.375 257.7526 l
f*
454.375 235.7527 m
391.6446 235.7527 l
391.6446 236.2527 l
454.375 236.2527 l
f*
516.7273 257.7526 m
516.7273 235.7527 l
516.2272 235.7527 l
516.2272 257.7526 l
f*
516.2272 235.7527 m
454.875 235.7527 l
454.875 236.2527 l
516.2272 236.2527 l
f*
576 235.7527 m
516.7273 235.7527 l
516.7273 236.2527 l
576 236.2527 l
f*
79.7267 235.7527 m
79.7267 204.2527 l
79.2266 204.2527 l
79.2266 235.7527 l
f*
79.2266 204.2527 m
36 204.2527 l
36 204.7527 l
79.2266 204.7527 l
f*
145.4924 235.7527 m
145.4924 204.2527 l
144.9924 204.2527 l
144.9924 235.7527 l
f*
144.9924 204.2527 m
79.7267 204.2527 l
79.7267 204.7527 l
144.9924 204.7527 l
f*
203.6183 235.7527 m
203.6183 204.2527 l
203.1182 204.2527 l
203.1182 235.7527 l
f*
203.1182 204.2527 m
145.4924 204.2527 l
145.4924 204.7527 l
203.1182 204.7527 l
f*
268.2663 235.7527 m
268.2663 204.2527 l
267.7663 204.2527 l
267.7663 235.7527 l
f*
267.7663 204.2527 m
203.6183 204.2527 l
203.6183 204.7527 l
267.7663 204.7527 l
f*
329.7917 235.7527 m
329.7917 204.2527 l
329.2917 204.2527 l
329.2917 235.7527 l
f*
329.2917 204.2527 m
268.2663 204.2527 l
268.2663 204.7527 l
329.2917 204.7527 l
f*
391.6446 235.7527 m
391.6446 204.2527 l
391.1445 204.2527 l
391.1445 235.7527 l
f*
391.1445 204.2527 m
329.7917 204.2527 l
329.7917 204.7527 l
391.1445 204.7527 l
f*
454.875 235.7527 m
454.875 204.2527 l
454.375 204.2527 l
454.375 235.7527 l
f*
454.375 204.2527 m
391.6446 204.2527 l
391.6446 204.7527 l
454.375 204.7527 l
f*
516.7273 235.7527 m
516.7273 204.2527 l
516.2272 204.2527 l
516.2272 235.7527 l
f*
516.2272 204.2527 m
454.875 204.2527 l
454.875 204.7527 l
516.2272 204.7527 l
f*
576 204.2527 m
516.7273 204.2527 l
516.7273 204.7527 l
576 204.7527 l
f*
79.7267 204.2527 m
79.7267 172.7527 l
79.2266 172.7527 l
79.2266 204.2527 l
f*
79.2266 172.7527 m
36 172.7527 l
36 173.2527 l
79.2266 173.2527 l
f*
145.4924 204.2527 m
145.4924 172.7527 l
144.9924 172.7527 l
144.9924 204.2527 l
f*
144.9924 172.7527 m
79.7267 172.7527 l
79.7267 173.2527 l
144.9924 173.2527 l
f*
203.6183 204.2527 m
203.6183 172.7527 l
203.1182 172.7527 l
203.1182 204.2527 l
f*
203.1182 172.7527 m
145.4924 172.7527 l
145.4924 173.2527 l
203.1182 173.2527 l
f*
268.2663 204.2527 m
268.2663 172.7527 l
267.7663 172.7527 l
267.7663 204.2527 l
f*
267.7663 172.7527 m
203.6183 172.7527 l
203.6183 173.2527 l
267.7663 173.2527 l
f*
329.7917 204.2527 m
329.7917 172.7527 l
329.2917 172.7527 l
329.2917 204.2527 l
f*
329.2917 172.7527 m
268.2663 172.7527 l
268.2663 173.2527 l
329.2917 173.2527 l
f*
391.6446 204.2527 m
391.6446 172.7527 l
391.1445 172.7527 l
391.1445 204.2527 l
f*
391.1445 172.7527 m
329.7917 172.7527 l
329.7917 173.2527 l
391.1445 173.2527 l
f*
454.875 204.2527 m
454.875 172.7527 l
454.375 172.7527 l
454.375 204.2527 l
f*
454.375 172.7527 m
391.6446 172.7527 l
391.6446 173.2527 l
454.375 173.2527 l
f*
516.7273 204.2527 m
516.7273 172.7527 l
516.2272 172.7527 l
516.2272 204.2527 l
f*
516.2272 172.7527 m
454.875 172.7527 l
454.875 173.2527 l
516.2272 173.2527 l
f*
576 172.7527 m
516.7273 172.7527 l
516.7273 173.2527 l
576 173.2527 l
f*
79.7267 172.7527 m
79.7267 150.7527 l
79.2266 150.7527 l
79.2266 172.7527 l
f*
79.2266 150.7527 m
36 150.7527 l
36 151.2527 l
79.2266 151.2527 l
f*
145.4924 172.7527 m
145.4924 150.7527 l
144.9924 150.7527 l
144.9924 172.7527 l
f*
144.9924 150.7527 m
79.7267 150.7527 l
79.7267 151.2527 l
144.9924 151.2527 l
f*
203.6183 172.7527 m
203.6183 150.7527 l
203.1182 150.7527 l
203.1182 172.7527 l
f*
203.1182 150.7527 m
145.4924 150.7527 l
145.4924 151.2527 l
203.1182 151.2527 l
f*
268.2663 172.7527 m
268.2663 150.7527 l
267.7663 150.7527 l
267.7663 172.7527 l
f*
267.7663 150.7527 m
203.6183 150.7527 l
203.6183 151.2527 l
267.7663 151.2527 l
f*
329.7917 172.7527 m
329.7917 150.7527 l
329.2917 150.7527 l
329.2917 172.7527 l
f*
329.2917 150.7527 m
268.2663 150.7527 l
268.2663 151.2527 l
329.2917 151.2527 l
f*
391.6446 172.7527 m
391.6446 150.7527 l
391.1445 150.7527 l
391.1445 172.7527 l
f*
391.1445 150.7527 m
329.7917 150.7527 l
329.7917 151.2527 l
391.1445 151.2527 l
f*
454.875 172.7527 m
454.875 150.7527 l
454.375 150.7527 l
454.375 172.7527 l
f*
454.375 150.7527 m
391.6446 150.7527 l
391.6446 151.2527 l
454.375 151.2527 l
f*
516.7273 172.7527 m
516.7273 150.7527 l
516.2272 150.7527 l
516.2272 172.7527 l
f*
516.2272 150.7527 m
454.875 150.7527 l
454.875 151.2527 l
516.2272 151.2527 l
f*
576 150.7527 m
516.7273 150.7527 l
516.7273 151.2527 l
576 151.2527 l
f*
79.7267 150.7527 m
79.7267 128.7527 l
79.2266 128.7527 l
79.2266 150.7527 l
f*
79.2266 128.7527 m
36 128.7527 l
36 129.2528 l
79.2266 129.2528 l
f*
145.4924 150.7527 m
145.4924 128.7527 l
144.9924 128.7527 l
144.9924 150.7527 l
f*
144.9924 128.7527 m
79.7267 128.7527 l
79.7267 129.2528 l
144.9924 129.2528 l
f*
203.6183 150.7527 m
203.6183 128.7527 l
203.1182 128.7527 l
203.1182 150.7527 l
f*
203.1182 128.7527 m
145.4924 128.7527 l
145.4924 129.2528 l
203.1182 129.2528 l
f*
268.2663 150.7527 m
268.2663 128.7527 l
267.7663 128.7527 l
267.7663 150.7527 l
f*
267.7663 128.7527 m
203.6183 128.7527 l
203.6183 129.2528 l
267.7663 129.2528 l
f*
329.7917 150.7527 m
329.7917 128.7527 l
329.2917 128.7527 l
329.2917 150.7527 l
f*
329.2917 128.7527 m
268.2663 128.7527 l
268.2663 129.2528 l
329.2917 129.2528 l
f*
391.6446 150.7527 m
391.6446 128.7527 l
391.1445 128.7527 l
391.1445 150.7527 l
f*
391.1445 128.7527 m
329.7917 128.7527 l
329.7917 129.2528 l
391.1445 129.2528 l
f*
454.875 150.7527 m
454.875 128.7527 l
454.375 128.7527 l
454.375 150.7527 l
f*
454.375 128.7527 m
391.6446 128.7527 l
391.6446 129.2528 l
454.375 129.2528 l
f*
516.7273 150.7527 m
516.7273 128.7527 l
516.2272 128.7527 l
516.2272 150.7527 l
f*
516.2272 128.7527 m
454.875 128.7527 l
454.875 129.2528 l
516.2272 129.2528 l
f*
576 128.7527 m
516.7273 128.7527 l
516.7273 129.2528 l
576 129.2528 l
f*
576 95.0026 m
36 95.0026 l
36 95.5026 l
576 95.5026 l
f*
0.83 0.64 0.02 0 k
36 81.9213 m
186.7465 81.9213 l
h
f*
0 g
7.9999 0 0 7.9999 36 329.1023 cm
BT
/F2 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Table)Tj
2.7992 0 Td
(1.)Tj
1.2614 0 Td
(Descriptio)Tj
4.8189 0 Td
(n)Tj
0.8292 0 Td
(of)Tj
1.1551 0 Td
(the)Tj
1.7008 0 Td
(population)Tj
5.2867 0 Td
(analyzed)Tj
4.3866 0 Td
(from)Tj
2.4166 0 Td
(the)Tj
1.6937 0 Td
(Enroll-HD)Tj
4.7764 0 Td
(database.)Tj
0 Tc
-17.0151 -1.8567 Td
(Non-HD)Tj
3.9331 0 Td
(individuals)Tj
5.4567 0 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8079 0 Td
(1384\))Tj
21.5081 0 Td
(HD)Tj
1.6653 0 Td
(patients)Tj
4.0536 0 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8079 0 Td
(5616\))Tj
-48.0547 -1.559 Td
(No)Tj
1.559 0 Td
(metformin)Tj
5.1024 0 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8079 0 Td
(1282\))Tj
2.7638 0 Td
(\(No)Tj
-7.0583 -1.1906 Td
(diabetes\))Tj
11.4733 1.1906 Td
(Metformi)Tj
4.2024 0 Td
(n)Tj
0.8433 0 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.815 0 Td
(102\))Tj
2.211 0 Td
(\(Type)Tj
2.8843 0 Td
(2)Tj
-7.9725 -1.1906 Td
(diabetes\))Tj
11.3528 1.1906 Td
(No)Tj
1.5591 0 Td
(metfor)Tj
3.0898 0 Td
(min)Tj
2.0055 0 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.815 0 Td
(5456\))Tj
2.7638 0 Td
(\(No)Tj
-7.0655 -1.1906 Td
(diabetes\))Tj
11.2678 1.1906 Td
(Metformi)Tj
4.2024 0 Td
(n)Tj
0.8434 0 Td
(\(n)Tj
1.1763 0 Td
(=)Tj
0.8079 0 Td
(160\))Tj
2.2182 0 Td
(\(Type)Tj
2.8842 0 Td
(2)Tj
-7.9796 -1.1906 Td
(diabetes\))Tj
-50.4996 -1.5591 Td
(Genotype)Tj
0.2835 -1.1905 Td
(negative)Tj
0.0354 -1.1906 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8079 0 Td
(644\))Tj
6.1654 2.3811 Td
(Family)Tj
-0.1134 -1.1905 Td
(control)Tj
-0.2976 -1.1906 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8149 0 Td
(638\))Tj
5.3717 2.3811 Td
(Genotyp)Tj
4.0465 0 Td
(e)Tj
-3.8197 -1.1905 Td
(Negative)Tj
0.3614 -1.1906 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8079 0 Td
(37\))Tj
4.2236 2.3811 Td
(Family)Tj
3.3875 0 Td
(control)Tj
-1.7079 -1.1905 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8078 0 Td
(65\))Tj
4.3371 1.1905 Td
(Pre-)Tj
2.1614 0 Td
(Manifest)Tj
-1.3252 -1.1905 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.815 0 Td
(1232\))Tj
6.5339 1.1905 Td
(Motor-)Tj
-0.4677 -1.1905 Td
(Manifest)Tj
-0.2339 -1.1906 Td
(\(n)Tj
1.1693 0 Td
(=)Tj
0.815 0 Td
(4224\))Tj
4.989 2.3811 Td
(Pre-)Tj
2.1614 0 Td
(Manifest)Tj
-0.7724 -1.1905 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8149 0 Td
(39\))Tj
5.7686 1.1905 Td
(Motor-)Tj
-0.4677 -1.1905 Td
(Manifest)Tj
0.0354 -1.1906 Td
(\(n)Tj
1.1764 0 Td
(=)Tj
0.8079 0 Td
(121\))Tj
-63.7942 -1.559 Td
(Age)Tj
/F0 1 Tf
5.9031 0 Td
(45.6)Tj
2.1615 0 Td
(\(14.47\))Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.3325 127.559 251.8299 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(a)Tj
ET
Q
q
1 j
1 J
0 w
7.9999 0 0 7.9999 132.6614 248.2582 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(46)Tj
-4.2236 -1.1905 Td
(\(34,)Tj
1.9417 0 Td
(56\))Tj
4.5567 1.1905 Td
(56.09)Tj
2.7142 0 Td
(\(11.72\))Tj
-2.5512 -1.1905 Td
(58)Tj
1.3323 0 Td
(\(49,)Tj
1.9417 0 Td
(64.5\))Tj
3.5717 1.1905 Td
(52.97)Tj
2.7142 0 Td
(\(12.92\))Tj
3.3732 0 Td
(53)Tj
-4.1811 -1.1905 Td
(\(44,)Tj
1.9417 0 Td
(63\))Tj
4.7056 1.1905 Td
(61.97)Tj
2.7071 0 Td
(\(10.38\))Tj
-2.1331 -1.1905 Td
(63)Tj
1.3323 0 Td
(\(55,)Tj
1.9418 0 Td
(69\))Tj
3.4724 1.1905 Td
(41.82)Tj
2.7142 0 Td
(\(11.9\))Tj
2.8205 0 Td
(41)Tj
-3.9047 -1.1905 Td
(\(33,)Tj
1.9417 0 Td
(51\))Tj
4.6347 1.1905 Td
(53.32)Tj
2.7142 0 Td
(\(12.56\))Tj
-2.1402 -1.1905 Td
(54)Tj
1.3323 0 Td
(\(45,)Tj
1.9418 0 Td
(62\))Tj
3.9685 1.1905 Td
(49.77)Tj
2.7142 0 Td
(\(13.05\))Tj
-2.5512 -1.1905 Td
(50)Tj
1.3323 0 Td
(\(38.5,)Tj
2.7709 0 Td
(58\))Tj
3.3378 1.1905 Td
(59.39)Tj
2.7142 0 Td
(\(10.92\))Tj
-2.1402 -1.1905 Td
(59)Tj
1.3323 0 Td
(\(52,)Tj
1.9417 0 Td
(68\))Tj
/F2 1 Tf
-64.7153 -1.5591 Td
(Sex)Tj
0 -1.1905 Td
(Female)Tj
0 -1.1835 Td
(Male)Tj
/F0 1 Tf
5.9244 2.374 Td
(470)Tj
1.878 0 Td
(\(73.0%\))Tj
3.7134 0 Td
(174)Tj
-3.7134 -1.1905 Td
(\(27.0%\))Tj
6.8031 1.1905 Td
(395)Tj
1.8851 0 Td
(\(61.9%\))Tj
-1.8851 -1.1905 Td
(243)Tj
1.8851 0 Td
(\(38.1%\))Tj
5.4 1.1905 Td
(24)Tj
1.3323 0 Td
(\(64.9%\))Tj
3.7063 0 Td
(13)Tj
-3.7063 -1.1905 Td
(\(35.1%\))Tj
6.5552 1.1905 Td
(23)Tj
1.3323 0 Td
(\(35.4%\))Tj
3.7063 0 Td
(42)Tj
-3.7063 -1.1905 Td
(\(64.6%\))Tj
6.7677 1.1905 Td
(813)Tj
1.8851 0 Td
(\(66.0%\))Tj
-1.8851 -1.1905 Td
(419)Tj
1.8851 0 Td
(\(34.0%\))Tj
5.6551 1.1905 Td
(2198)Tj
2.4379 0 Td
(\(52.0%\))Tj
-2.4379 -1.1905 Td
(2026)Tj
2.4379 0 Td
(\(48.0%\))Tj
5.2654 1.1905 Td
(26)Tj
1.3322 0 Td
(\(66.7%\))Tj
3.7064 0 Td
(13)Tj
-3.7064 -1.1905 Td
(\(33.3%\))Tj
6.2718 1.1905 Td
(58)Tj
1.3322 0 Td
(\(47.9%\))Tj
3.7064 0 Td
(63)Tj
-3.7064 -1.1905 Td
(\(52.1%\))Tj
/F2 1 Tf
-62.0578 -2.7497 Td
(Body)Tj
0 -1.1834 Td
(Mass)Tj
0 -1.1906 Td
(Index)Tj
/F0 1 Tf
6.8882 2.374 Td
(27.67)Tj
2.7142 0 Td
(\(6.44\))Tj
-3.6567 -1.1834 Td
(26.5)Tj
2.1614 0 Td
(\(23.4,)Tj
2.7709 0 Td
(30.8\))Tj
3.7559 1.1834 Td
(28.88)Tj
2.7141 0 Td
(\(6.16\))Tj
-3.2456 -1.1834 Td
(28)Tj
1.3322 0 Td
(\(24.7,)Tj
2.7709 0 Td
(31.6\))Tj
4.1032 1.1834 Td
(36.05)Tj
2.7142 0 Td
(\(8.09\))Tj
-3.2457 -1.1834 Td
(34.6)Tj
2.1614 0 Td
(\(31.6,)Tj
2.7709 0 Td
(39\))Tj
3.4867 1.1834 Td
(34.04)Tj
2.7071 0 Td
(\(6.39\))Tj
-2.6859 -1.1834 Td
(32.7)Tj
2.1615 0 Td
(\(29.62,)Tj
-0.9355 -1.1906 Td
(37.78\))Tj
5.9316 2.374 Td
(26.8)Tj
2.1614 0 Td
(\(5.6\))Tj
2.2748 0 Td
(25.8)Tj
-4.0465 -1.1834 Td
(\(22.75,)Tj
3.3237 0 Td
(29.8\))Tj
3.8268 1.1834 Td
(25.04)Tj
2.7142 0 Td
(\(5.1\))Tj
2.2748 0 Td
(24.3)Tj
-4.3229 -1.1834 Td
(\(21.6,)Tj
2.778 0 Td
(27.58\))Tj
5.1804 1.1834 Td
(33.06)Tj
2.7142 0 Td
(\(6.54\))Tj
-2.4095 -1.1834 Td
(32.4)Tj
2.1614 0 Td
(\(28.4,)Tj
-0.9425 -1.1906 Td
(36.5\))Tj
6.3567 2.374 Td
(29.5)Tj
2.1615 0 Td
(\(6.05\))Tj
-2.4166 -1.1834 Td
(28.85)Tj
2.7142 0 Td
(\(25.1,)Tj
-0.8008 -1.1906 Td
(32\))Tj
/F2 1 Tf
-63.0783 -1.5591 Td
(ISCED)Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.3325 62.1921 166.7905 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(b)Tj
ET
Q
q
1 j
1 J
0 w
7.9999 0 0 7.9999 84.6425 163.2755 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(4.03)Tj
2.1614 0 Td
(\(1.14\))Tj
2.8276 0 Td
(4)Tj
0.7795 0 Td
(\(3,)Tj
-2.7425 -1.1905 Td
(5\))Tj
5.4142 1.1905 Td
(3.89)Tj
2.1614 0 Td
(\(1.19\))Tj
2.8276 0 Td
(4)Tj
-3.3591 -1.1905 Td
(\(3,)Tj
1.3961 0 Td
(5\))Tj
3.9473 1.1905 Td
(3.27)Tj
2.1614 0 Td
(\(1.41\))Tj
2.8276 0 Td
(3)Tj
0.7795 0 Td
(\(3,)Tj
-2.7425 -1.1905 Td
(4\))Tj
5.5559 1.1905 Td
(3.75)Tj
2.1614 0 Td
(\(1.24\))Tj
2.8276 0 Td
(4)Tj
-3.352 -1.1905 Td
(\(3,)Tj
1.389 0 Td
(5\))Tj
4.6914 1.1905 Td
(3.91)Tj
2.1614 0 Td
(\(1.13\))Tj
2.8205 0 Td
(4)Tj
-3.352 -1.1905 Td
(\(3,)Tj
1.389 0 Td
(5\))Tj
4.0961 1.1905 Td
(3.37)Tj
2.1614 0 Td
(\(1.23\))Tj
2.8276 0 Td
(3)Tj
0.7796 0 Td
(\(2,)Tj
-2.7426 -1.1905 Td
(4\))Tj
5.4922 1.1905 Td
(3.85)Tj
2.1614 0 Td
(\(1.11\))Tj
2.8276 0 Td
(4)Tj
-3.3591 -1.1905 Td
(\(3,)Tj
1.3961 0 Td
(5\))Tj
4.578 1.1905 Td
(3.31)Tj
2.1614 0 Td
(\(1.35\))Tj
2.8205 0 Td
(3)Tj
-3.352 -1.1905 Td
(\(2,)Tj
1.389 0 Td
(5\))Tj
/F2 1 Tf
-64.0492 -1.5591 Td
(CAG)Tj
0 -1.1905 Td
(repeats)Tj
/F0 1 Tf
6.2291 1.1905 Td
(20.22)Tj
2.7071 0 Td
(\(3.66\))Tj
2.8276 0 Td
(19)Tj
-3.9048 -1.1905 Td
(\(18,)Tj
1.9418 0 Td
(22\))Tj
4.8331 1.1905 Td
(20.05)Tj
2.7142 0 Td
(\(3.41\))Tj
-2.4166 -1.1905 Td
(19)Tj
1.3323 0 Td
(\(17,)Tj
1.9417 0 Td
(22\))Tj
3.4371 1.1905 Td
(20.65)Tj
2.7142 0 Td
(\(3.03\))Tj
2.8205 0 Td
(21)Tj
-3.9048 -1.1905 Td
(\(18,)Tj
1.9418 0 Td
(22\))Tj
4.3157 1.1905 Td
(20.15)Tj
2.7071 0 Td
(\(3.83\))Tj
2.8276 0 Td
(19)Tj
-3.9047 -1.1905 Td
(\(17,)Tj
1.9417 0 Td
(22\))Tj
4.1386 1.1905 Td
(42.29)Tj
2.7142 0 Td
(\(2.72\))Tj
2.8205 0 Td
(42)Tj
-3.9047 -1.1905 Td
(\(41,)Tj
1.9417 0 Td
(43\))Tj
4.2449 1.1905 Td
(44.03)Tj
2.7142 0 Td
(\(3.95\))Tj
2.8205 0 Td
(43)Tj
-3.9047 -1.1905 Td
(\(42,)Tj
1.9417 0 Td
(45\))Tj
4.2449 1.1905 Td
(40.87)Tj
2.7142 0 Td
(\(2.12\))Tj
2.8276 0 Td
(41)Tj
-4.3229 -1.1905 Td
(\(39.5,)Tj
2.7709 0 Td
(42\))Tj
3.6142 1.1905 Td
(42.34)Tj
2.7142 0 Td
(\(2.33\))Tj
2.8205 0 Td
(42)Tj
-3.9047 -1.1905 Td
(\(41,)Tj
1.9417 0 Td
(43\))Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.3325 36 116.5606 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(a)Tj
ET
Q
q
1 j
1 J
0 w
7.9999 0 0 7.9999 41.159 112.9889 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(Data)Tj
2.3244 0 Td
(are)Tj
1.6653 0 Td
(presented)Tj
4.6418 0 Td
(as)Tj
1.2827 0 Td
(mean)Tj
2.7071 0 Td
(\(SD\))Tj
2.2748 0 Td
(and)Tj
1.8851 0 Td
(median)Tj
3.4795 0 Td
(\(1st,)Tj
2.1686 0 Td
(3rd)Tj
1.6653 0 Td
(quartile\).)Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.3325 36 104.5417 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(b)Tj
ET
Q
q
1 j
1 J
0 w
7.9999 0 0 7.9999 41.159 101.0267 cm
BT
/F0 1 Tf
1 TL
0 0 Td
(Interna)Tj
3.0897 0 Td
(tional)Tj
2.6008 0 Td
(Standard)Tj
4.2591 0 Td
(Classica)Tj
4.2449 0 Td
(tion)Tj
1.8284 0 Td
(of)Tj
1.063 0 Td
(Education)Tj
4.6418 0 Td
(promoted)Tj
4.4291 0 Td
(by)Tj
1.2756 0 Td
(UNESCO)Tj
4.4859 0 Td
(to)Tj
1.063 0 Td
(standardis)Tj
4.578 0 Td
(e.)Tj
0.83 0.64 0.02 0 k
/F10 1 Tf
-0.025 Tc
-38.2041 -2.2535 Td
(https://do)Tj
3.5574 0 Td
(i.org/10.1371/j)Tj
5.4425 0 Td
(ournal.pone)Tj
4.4079 0 Td
(.0179283.t001)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 451.8992 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Metformin)Tj
4.5992 0 Td
(and)Tj
1.8567 0 Td
(Huntingto)Tj
4.1953 0 Td
(n's)Tj
1.474 0 Td
(disease)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.01792)Tj
4.089 0 Td
(83)Tj
0 g
2.0906 0 Td
(June)Tj
2.3528 0 Td
(20,)Tj
1.5874 0 Td
(2017)Tj
34.9656 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
76 0 obj
<>stream
endstream
endobj
77 0 obj
<>stream
endstream
endobj
78 0 obj
<>stream
endstream
endobj
79 0 obj
<>stream
endstream
endobj
80 0 obj
<>stream
endstream
endobj
81 0 obj
<>stream
BT
66.402 0 Td
(11)Tj
ET
Q
endstream
endobj
82 0 obj
<>/ColorSpace<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 85 0 R/Contents 86 0 R/TrimBox[0 0 612 792]>>
endobj
84 0 obj
[/ICCBased 87 0 R]
endobj
87 0 obj
<>stream
xwTSϽ7PkhRH
H.*1 J "6DTpDQ2(C"QDqpIdy͛~kg}ֺ LX Xňg` l pBF|،l *? Y"1 P\8=W%Oɘ4M0J"Y2Vs,[|e92<se'9`2&ctI@o|N6 (.sSdl-c(2-y H_/XZ.$&\SM07#1ؙYr fYym";8980m-m(]v^DW~
emi ]P`/ u}q|^R,g+\Kk)/C_|Rax8t1C^7nfzDp柇u$/ED˦L L[B@ٹЖX!@~ (* {d+}G͋љς}WL$cGD2QZ4 E@@ A(q`1D `'u46ptc48.`R0)
@Rt CXCP%CBH@Rf[(t
CQhz#0 Zl`O828.p|O×X
?:0FBx$ !i@ڐH[EE1PL⢖V6QP>U(j
MFk t,:.FW8c1L&ӎ9ƌaX:
rbl1
{{{;}#tp8_\8"Ey.,X%%Gщ1-9ҀKl.oo/O$&'=JvMޞ